The Renin-Angiotensin Aldosterone System in Various Disorders

#### **Chapter 3**

## Role of the Renin-Angiotensin-Aldosterone System in Various Disease Processes: An Overview

*Volkan Gelen, Abdulsamed Kükürt and Emin Şengül*

#### **Abstract**

The renin-angiotensin-aldosterone system is a physiological system that plays an important role in the regulation of blood pressure and body water-electrolyte balance, in which the kidney, liver and lungs play a role in its activation. This system comes into play in various diseases such as the cardiovascular, renal, pulmonary and nervous system where blood pressure and fluid-electrolyte balance may change. The purpose of this study, which is presented in line with this information, is to explain the working principle of this system, how this system is activated, how it comes into play in the mentioned diseases, and what kind of results occur.

**Keywords:** Renin, angiotensin, aldosterone, ACE2, hypertension, pulmonary diseases, renal diseases, neurodegenerative diseases, AngII, Covid-19

#### **1. Introduction**

The renin-angiotensin-aldosterone system (RAAS) is a powerful system that regulates fluid-electrolyte balance and systemic blood pressure. First, it has been stated that it is a hormonal and peptidergic endocrine system that regulates blood pressure and fluid-electrolyte balance [1, 2]. Until recently, RAAS was known only as an endocrine system that regulates blood pressure and fluid-electrolyte balance, but now it is noted that this system is not only found in circulation but also locally in organ systems, and also has autocrine-paracrine functions [3].

There are some components of RAAS responsible for these effects. One of these components, renin, is synthesised as prorenin from the juxtaglomerular apparatus, which is also found in kidney efferent arterioles. The protein is converted to active renin, stored in secretory granules and released into the circulation when necessary [4]. The release of renin, a proteolytic enzyme, is triggered by many physiological stimuli, including prostacyclins (PGI2), such as stimulation of macula densa in the distal tubule with low Na + concentration, reduction of arterial pressure, renal sympathetic nerve activation and stimulation of β1-receptors [5]. Circulating renin provides the formation of Angiotensin I (AngI) from angiotensinogen, most of which is synthesised from the liver [6]. AngI is converted to Angiotensin II (AngII) by Angiotensin-converting enzyme (ACE), a membrane-bound metalloproteinase found in high amounts on pulmonary vascular endothelial cell surfaces (**Figure 1**) [5, 7].

**Figure 1.** *Renin-angiotensin-aldosterone system and effects.*

ACE, a member of the zinc metallopeptidase class, had two main roles in metabolism. It takes part in the RAAS system and the kinin-kallikrein system (KKS). Another task is to inactivate substance P and neurokines [8, 9]. ACE has two forms in endothelial and epithelial cells and male spermatid. Its form in endothelial and epithelial cells is called "somatic form" (sACE), and the form found in spermatids is called "germinal form" (gACE) [10]. The primary structure of these two forms is different from each other. While sACE has two active sites with different catalytic properties, gACE has only one active [11]. ACE has another mammalian homologue named angiotensin-converting enzyme 2 (ACE2) [12]. Although ACE2 has carboxypeptidase activity like ACE, it cleaves an amino acid unlike ACE and its most important substrates are AngI and AngII [13].

In the body, AngII has many roles such as increasing blood pressure by direct contraction of vascular smooth muscles, increasing myocardial contractility, water and salt retention by stimulating aldosterone release from the adrenals, stimulation of catecholamine release from sympathetic nerve endings, cell growth and proliferation [14, 15]. It turns out that AngII can be generated locally in many tissues, including the brain, independent of circulating components [16]. AngII acts by binding to receptors in the protein structure on the plasma membranes of different tissues. These receptors are termed AngII type 1 (AT1R) and AngII type 2 (AT2R) receptors [17]. Changes in the balance of RAAS have been reported to have direct or indirect effects with cardiovascular system diseases, lung diseases, nervous system diseases and kidney diseases. Therefore, this section describes the mechanism of action of RAAS and the relationship of RAAS components with these diseases.

#### **2. The role of RAAS in cardiovascular disease**

#### **2.1 Heart failure and myocardial infarction**

Ang II has a role in a variety of cardiac dysfunctions, including hypertrophy, arrhythmia, and ventricular dysfunction [18, 19]. Inability to pump enough blood *Role of the Renin-Angiotensin-Aldosterone System in Various Disease Processes: An Overview DOI: http://dx.doi.org/10.5772/intechopen.97354*

to the body due to insufficient heart functions due to various reasons is known as heart failure. When looking at the role of RAAS in the case of heart failure, RAAS activation can occur when hypertrophy occurs in the heart muscle cells. This causes fluid retention in the body and peripheral vasoconstriction, resulting in cardiac overload and heart failure [20]. RAAS activation increases in heart rate and contractility, thus reducing coronary blood flow [21]. Experimental studies have shown that plasma renin activity increases in acute heart failure. Also, it was determined that plasma renin activity was normal in the compensated phase of chronic heart failure, and this shows that RAAS is associated with heart failure [22]. It has also been determined that when myocardial cells are exposed to excessive AngII and aldosterone, fibrosis is formed. This again shows that RAAS plays an important role in myocardial heart disease. It was determined that AT-1 receptor expression affected by AngII decreased in decompensated heart failure, while AT-2 receptors remained unchanged [23]. It has also been determined that ACE inhibitors play an important role in heart failure. It has been reported that ACE inhibitors are beneficial, especially in patients with left ventricular failure, and that death rates are reduced [24]. These findings are an important indicator that renin-angiotensin inhibition is crucial to improving cardiac dysfunction. When the relationship of RAAS with myocardial infarction is examined, it has been determined that ACE2 RNA expression increases in the case of myocardial infarction [25]. In another study, it was shown that ACE2 expression increased in the case of myocardial injury induced by ischemia–reperfusion in rats and this increase attenuated myocardial damage [26].

#### **2.2 Hypertension**

It has been determined that the plasma renin level changes in the case of hypertension. Plasma renin levels are not proportional to blood pressure, and it has been reported that plasma renin levels are low in some patients, normal in others and high in others. One of the reasons for the change in the renin level is that it is primarily caused by ischemia that develops in the nephrons. In this case, renin levels released from ischemic nephrons increase at different levels, resulting in normal or high plasma renin levels. The renin released from ischemic nephrons passes into the circulation leading to the formation of AngII [17, 27]. As a result, hypertension occurs with increased vasoconstriction and sodium retention in nephrons. The reason why plasma renin level is normal in some hypertensive patients is that aldosterone is not synthesised in response to sodium restriction. Also, it has been stated that resistance to renin and AngII is formed in the vessels and therefore they can increase blood pressure even at low levels. Besides, independent of RAAS in circulating blood, it has been determined that Ang II production by serine protein kinase activity is independent of ACE activity in the heart, brain, adrenal cortex and blood vessels [28]. Also, AngII contributes to hypertension [29]. When looking at the relationship between salt intake and RAAS, it is seen that high salt intake suppresses RAAS, while low salt intake stimulates AngII release [30]. Studies have determined that smooth muscle cells are also critical in the regulation of AngII-mediated blood pressure. A study in mice found that 22α protein deficiency in smooth muscle reduces hypertension that can occur with AngII [31]. This is an indication that the RAAS system plays an important role in hypertension.

#### **2.3 Atherosclerosis**

AngII has been determined to induce endothelial dysfunction and increase oxidative stress in the endothelium by stimulating the production of reactive oxygen

species (ROS) such as superoxide anions (O2−) derived from nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). This is especially the result of endothelial AT1R stimulation that interacts with the Nox5/Ca2 + calmodulin binding site, which will increase Ca + concentration in the endothelial cell [32, 33]. Nox5 is a member of the NADPH oxidase family and plays an important role in the development of atherosclerosis, inflammation, and oxidative stress [33, 34]. It also plays a role in the adhesion of mononuclear cells to the arterial endothelium and recruitment of mononuclear cells by stimulating the increase in CAM expression of TNF-α, which is released as a result of stimulation of AT1R with AngII, in combination with IL-6 [35]. One study reported that AngII induced monocyte chemotactic protein-derived protein expression (MCPIP1) via an AMPK/p38 MAPK-dependent pathway [36]. Increased MCPIP1 expression contributes to atherosclerotic plaque formation by triggering apoptosis in macrophages [37]. Another thing related to the formation of atherosclerosis is that AngII induces the expression of a multifunctional protein found in macrophages, endothelial cells, smooth muscle cells (SMCs), and epithelial cells called osteopontin. Osteopontin plays an important role in the development and development of atherosclerosis [38]. The cell membrane has a transmembrane glycoprotein called LOX. LOX acts as a receptor for oxidised LDL (oxLDL). It increases the expression of AngII LOX-1 gene. Binding of oxLDL to LOX-1 in the endothelium causes an increase in leukocyte adhesion molecules, activates apoptosis pathways, increases ROS and induces endothelial dysfunction. This situation contributes to the development of atherosclerosis. Also, oxLDL increases the formation of ACE, which induces the formation of AngII (**Figure 2**). This increases LOX-1 expression, which positively regulates the expression of AT1R, and contributes to a self-sustaining pro-atherogenic cycle [39]. Thus, it has been determined that ACE and ATR1 inhibitors prevent the development of atherosclerosis.

#### **2.4 Vascular inflammation**

RAAS plays an important role in shaping vascular inflammation. Vascular inflammation causes endothelial dysfunction. This dysfunction causes tissue damage. Endothelial dysfunction also results in the accumulation of inflammatory cells in the area. This situation triggers atherosclerosis. Also, studies have shown that

#### **Figure 2.**

*Mechanism of AngII-mediated atherosclerosis formation. Involvement of Ang-II, ACE2, and Ang-1–7 in atherogenic pathways. The Ang-II binding into AT1R can activate Nox5 through a calcium/calmodulindependent pathway.*

*Role of the Renin-Angiotensin-Aldosterone System in Various Disease Processes: An Overview DOI: http://dx.doi.org/10.5772/intechopen.97354*

AngII-mediated inflammation and hypertension and atherosclerosis develop [40]. In another study, it was determined that AngII administration in human vascular smooth muscle cells increased NF-KB activation, thus increasing IL-6, MCP-1 and TNF-expression [41]. Again, although it is a vasoconstrictor, AngII was determined to induce endothelial damage by inhibiting endothelial cell regeneration. AngII has been reported to act as a second messenger to activate intracellular signalling pathways such as mitogen-activated protein kinase (MAPK) and protein kinase Akt/ protein kinase B (Akt/PKB), pathways that mediate cell proliferation and apoptosis, and thus vascular dysfunction [42]. AngII is also stated to be a potent pro-oxidant. Ang II induces the production of superoxide anions and activates NADH/NADPH signalling [43]. AngII lowers nitric oxide (NO) levels and activates redox-sensitive genes, particularly cytokines and adhesion molecules [44]. Ang II is also a profibrotic factor. Chronic AngII administration in mice has been shown to cause an increase in blood pressure, infiltration of inflammatory cells into the myocardium and cardiac fibrosis [45]. Another factor that provides the proinflammatory and profibrinolytic effect of RAAS in vessels is aldosterone [46]. Aldosterone affects insulin resistance and the development of atherosclerosis. In vascular smooth muscle cells, aldosterone alters insulin signalling, increases insulin-like growth factor-1 expression.

#### **2.5 Oxidative stress**

Oxidative stress is defined as the disproportion between the presence of antioxidants and free radicals or prooxidants in a biological system. ROS and reactive nitrogen species (RNTs) are by-products of a variety of cellular processes, including aerobic metabolism [47–51]. These by-products cause damage to various tissues [52–73]. RAAS has a direct relationship with oxidative stress that may occur in the cardiovascular system. It has been determined that chronic administration of aldosterone, one of the components of RAAS, causes oxidative stress in the rat aorta [74]. AngII represents one of the major vasoactive peptides involved in the regulation and activation of NADPH oxidase. Ang II stimulates the activation of NADPH oxidase, increases the expression of NADPH oxidase subunits, and induces ROS formation in vascular smooth muscle cells, endothelial cells and fibroblasts. ACE2 shows an effect of reducing oxidative stress by inhibition of ROS synthesis by reducing AngII to Ang 1–7. Ang 1–7 therapy can have a curative effect on vascular disease models. It is reported that solutions that can increase Ang 1–7 levels may be beneficial to alleviate endothelial dysfunction [75]. This is supported by studies showing that overexpression of ACE2 leads to attenuating the effects of hypertension in animal models [76, 77]. It supports the argument that hypertension is a side effect directly related to oxidative stress, thus overexpression of ACE2 leads to a reduction of oxidative stress in a biological system [78].

#### **3. The role of RAAS in renal diseases**

#### **3.1 Proteinuria**

RAAS plays an important role in the pathogenesis of many kidney diseases characterised by proteinuria. In a study, it was stated that AngII induces the formation of proteinuria. It has also been determined that AngII stimulates the formation of TGF-1 in various kidney cells [79]. TGF-1 has been found to impair autoregulation by afferent arterioles [80]. Vasoconstriction occurs after increased arterial

pressure in afferent arterioles. In case of impaired autoregulation in the presence of TGF-1, especially systemic hypertension occurs, an increase in transcapillary pressure occurs. Thus, AngII increases capillary filtration pressure by causing efferent vasoconstriction and TGF-1-mediated impaired afferent arteriole autoregulation. Also, AngII has been found to have a direct effect on the integrity of the filtration barrier. Again, AngII has been shown to reduce the synthesis of negatively charged proteoglycans and additionally suppress nephrin synthesis [81]. It has been observed that this situation causes apoptosis in podocytes. Vascular endothelial growth factor (VEGF) has been identified to be an important factor in increasing the permeability of the filtration barrier in the kidneys [82]. It has been determined to stimulate VEGF expression via the AngII, AT1 and AT 2 receptors. It is thought that the increase in VEGF expression via AT2 receptors may be mediated by an increase in hypoxia-inducible factor 1. Also, VEGF and TGF-1 mediate the AngIImediated synthesis of the 3rd chain of collagen type IV, which is a component of the glomerular basement membrane [83, 84]. As a result, it is seen that AngII causes proteinuria by causing changes in hemodynamic and non-hemodynamic mechanisms. AngII stimulates albumin reabsorption in proximal tubule cells through AT2 receptor-mediated protein kinase B activation [85]. Albumin uptake induces a selection of proinflammatory and profibrogenic cytokines such as monocyte chemoattractant protein-1, IL-8, endothelin, and TGF-1 [86]. This situation stimulates the migration of cells into the interstitium. Ultimately it causes inflammation in the interstitial area.

#### **3.2 Fibrosis**

In a study, ECM proteins induce type I procollagen and mRNA encoding fibronectin in cultured mesangial cells of AngII, and also stimulates the synthesis of type I collagen types 1 and 3 in cultured proximal tubular cells [79]. It has been determined that the stimulatory effect of AngII on collagen expression is dependent on TGF-1 expression. As a result of the studies, it has been reported that AngII stimulates the proliferation of cultured renal fibroblasts and increases mRNA expression of TGF-β1, fibronectin and type I collagen. It has also been observed that renin increases TGF-1 expression by stimulating a particular receptor in cultured mesangial cells [87]. These findings suggest that increased renin as a result of ACE inhibitor therapy may directly contribute to renal fibrosis through increased TGF-1 despite AngII blockade. It was also determined that AngII increased connective tissue growth factor (CTGF) in kidney tissue. CTGF is a fibrinolytic mediator and is also stimulated by TGF-β. However, AngII also stimulates CTGF synthesis independently of TGF-β [88]. These findings suggest that increased renin as a result of ACE inhibitor therapy may directly contribute to renal fibrosis through increased TGF-1 despite AngII blockade. It was also determined that AngII increased connective tissue growth factor (CTGF) in kidney tissue. CTGF is a fibrinolytic mediator and is also stimulated by TGF-β. However, AngII also stimulates CTGF synthesis independently of TGF-β [89]. Studies have shown that more than one-third of local fibroblasts in renal interstitial fibrosis originate from tubular epithelial cells through a process called epithelial to mesenchymal transition (EMT). Again, AngII can be effective on EMT [90].

#### **3.3 Inflammation**

Studies have shown that AngII activates the proinflammatory transcription factor NF-KB via AT1 and AT2 [91]. It has also been stated that it can stimulate *Role of the Renin-Angiotensin-Aldosterone System in Various Disease Processes: An Overview DOI: http://dx.doi.org/10.5772/intechopen.97354*

NF-KB in AngIII and AngIV [86]. It has been determined that Rho-kinase plays a role in AngII mediated NF-KB activation. Also, AngII stimulates the transcription factor Ets. This factor regulates vascular inflammation by the transport of T cells and macrophages to the vascular wall. AngII has been reported to increase the level of Toll-like 4 receptors that bind LPS on mesangial cells. It has been observed that this receptor has an increasing effect on NF-KB activation [92]. The penetration of inflammatory cells into the glomerulus as well as the tubulointerstitium plays an important role in the progression of chronic kidney disease. Also, AngII induces the adhesion of circulating immune cells to capillaries by stimulating the increase of adhesion molecules such as vascular cellular adhesion molecule-1, intracellular adhesion molecule-1 and integrins. This situation shows the relationship of AngII with renal inflammation. It has also been determined that AngII has a stimulating effect on lymphocyte production [86, 93].

#### **3.4 Chronic kidney disease (CKD)**

Studies explaining the relation of RAAS with CKD were made in the 1980s and important data were obtained in these studies [94]. AngII has emerged as a central mediator of kidney damage because it can induce glomerular capillary hypertension that damages endothelial, glomerular epithelial cells, and mesangial cells [94, 95]. Also, AngII/aldosterone has non-haemodynamic effects that are important in the pathogenesis of CKD, such as inflammation, fibrosis, ROS production, and activation of pathways associated with endothelial dysfunction [94]. One of the most common causes of CKD is diabetic nephropathy. RAAS has an important role in diabetic nephropathy. Plasma renin activity is lower than normal in patients with diabetes [96]. However, intra-renal RAAS activity is high [97, 98]. This is an indication that diabetic nephropathy has one of the most important roles in the formation of CKD.

#### **Figure 3.**

*Mechanism of AngII-mediated apoptosis formation in the podocyte. AT1R signalling induces ER stress through increased GRP 78 and p-elf2*α *expression and PKC-*δ *phosphorylation. p38 MAPK and PKC-*δ *activation lead to increased Bax expression and enhanced NHE1 activity, triggering cellular apoptosis.*

#### **3.5 Apoptosis**

Studies show that the RAAS system is associated with renal hypertrophy and apoptosis. It has been determined that AngII, one of the components of RAAS, induces apoptosis in vivo and in vitro conditions [99]. It has been reported that AT1 and AT2 receptors are involved in these effects. Studies have reported that Ang II plays an important role in tubular cells and podocytes in (Endoplasmic reticulum) ER stress-induced renal apoptosis, especially in diabetic nephropathy [100]. It has been shown that Ang II can induce podocyte ER stress via the PERK-eIf2-α-ATF4 axis and the PI3-kinase pathway [101]. Another study found an AT1R-mediated increase in glomerular GRP 78 in rats chronically treated with AngII. These data support the relationship between the AngII/AT1R signal and ER stress on podocyte damage. In the same study, Ang II treatment was reported to induce p38 MAPKdependent apoptosis in podocytes associated with Bax protein activation. In addition, Na+/H+ exchanger isoform 1 (NHE1) activity increases. As a result, it triggers cellular apoptosis (**Figure 3**), [102].

#### **4. The role of RAAS in lung diseases**

#### **4.1 Acute lung injury and pneumonia**

As a result of RAAS activation, inflammation [103] and vascular permeability increase [104] due to Ang II stimulation of AT1 receptor and thus severe acute lung damage occurs [105, 106]. In mice, administration of losartan prevents acute lung injury caused by Ang II and decreases AT1R expression [107, 108]. Pneumonia is associated with RAAS, especially in influenza-induced types of pneumonia RAAS system plays a very important role. In patients with pneumonia, the use of RAAS inhibitors reduces the mortality rate and the likelihood of intubation [109]. As with other viral types of pneumonia, children infected with the Respiratory syncytial virus (RSV) tend to have higher Ang II levels than healthy children [110]. The benefit of recombinant ACE2 treatment on RSV infection has been demonstrated in a preclinical mouse model in animal experiments [111]. H7N9 and H5N1 influenza reduce the level of ACE2, increase the level of Ang II, and thus cause lung damage via the AT1 receptor [112]. In H5N1 and H7N9 mouse models, treatment with losartan results in a decrease in IL-6 level and lung oedema, thus preventing lung damage [113]. It was concluded that losartan prevents lung damage by inhibiting RAAS activity.

#### **4.2 SARS-CoV viral infection**

The Spike protein [S protein] on the SARS-CoV Virus surface attaches to the ACE2 receptor and enters the body in this way. Moreover, ACE2 improves the efficiency of SARS-CoV replication [114]. Transmembrane protease serine 2 (TMPRSS2) can degrade ACE2 and S protein for membrane fusion and the entry of SARS-CoV into cells. Therefore, the concentration of ACE2 in the membrane decreases, but the number of cells infected with SARS-CoV with cessation increases [115]. Ang-II level increases in lung tissue of mice infected with SARS-CoV. Also, the use of angiotensin receptor blockers in these animals significantly reduces pulmonary oedema. This indicates that lung failure caused by SARS-CoV is caused by an increase in Ang-II level and overactivation of the AT1 receptor [116]. Increased ACE level and decreased ACE2 levels in SARS patients cause increased Ang II level

*Role of the Renin-Angiotensin-Aldosterone System in Various Disease Processes: An Overview DOI: http://dx.doi.org/10.5772/intechopen.97354*

and AT1 receptor expression, which accelerates lung damage and can lead to death [117]. Also, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), caspase 3 (CASP3), caspase 9 (CASP9) and fibroblast growth factor-7 (FGF-7) increase in the lung tissue of these patients [118].

#### **4.3 SARS-CoV-2 viral infection**

SARS-CoV-2 (Covid-19) Similar to SARS-CoV, the S protein uses the ACE2 cellular membrane for input and uses TMPRSS2 for S protein preparation to facilitate the fusion of viral and cellular membranes [119–121]. Compared to other coronaviruses, the affinity of S protein to ACE2 is higher in SARS-CoV and SARS-CoV-2. Looking at the distribution of ACE2 receptors in the body, it is found on the endothelial cells and smooth muscle cells of organs and tissues, including the oral and nasal mucosa, lung, small intestine, kidney, heart and blood vessels. The widespread distribution of ACE2 receptors in the body is an indicator of multi-organ failure in COVID-19 patients [122–124]. SARS-CoV-2 infection causes RAAS disorders and systemic inflammatory response. The plasma Ang II level of COVID-19 patients is significantly higher than that of healthy individuals. This condition is linearly related to viral load and lung injury [125]. A clinical study has shown that cytokine storm syndrome (CSS) occurs in patients with COVID-19 and severe pneumonia. Also, it showed that some cases can progress rapidly to Acute respiratory distress syndrome (ARDS) and even to multiple organ failure [126]. Inflammatory cytokines and chemokines are synthesised in Covid-19 patients, including IL-6, IL-2, IL-1β, IL-8, IL-17, IFN-γ, TNF-α and monocyte chemoattractant protein-1 (MCP-1) (**Figure 4**). Among them, however, IL-6 in particular plays a key role in triggering the inflammatory response, increasing the mortality rate in patients [125]. In Covid-19 infection, after the virus binds to ACE2 on the cell surface, Ang II cannot convert to Ang1–7, and thus more and more binding occurs to AT1 receptors. This situation causes an imbalance in the ACE/ Ang II/AT1R axis. As a result, the pulmonary endothelium and epithelial cells are damaged by stimulating inflammatory signalling pathways, resulting in an increase in the permeability of pulmonary capillaries [127].

**Figure 4.** *Effects of the renin-angiotensin system during SARS-CoV-2 infection.*

#### **5. The role of RAAS in some neurological disorders**

Brain RAAS irregularity may contribute to neurodegeneration due to neuroinflammation, oxidative stress and pathophysiological changes due to ageing. Several studies have reported that irregular RAAS plays a key role in numerous degenerative diseases of the brain, including Alzheimer's, Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, Multiple sclerosis, Traumatic brain injury, and Stroke [128–130].

#### **5.1 Alzheimer's disease**

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by impaired daily functions and behaviour, especially memory [131]. The most important change in AD neuropathology is Aβ-centred senile amyloid plaques formed in the hippocampus, amygdala and cortex. Neurovascular disorders and chronic neurodegeneration occur in the surrounding brain tissues and vessels as a result of the toxic effects of these plaques [132]. Besides these plaque formations; Neurofibrillary tangles, oxidative stress in cell membranes and organelles, inflammation, gliosis, excitotoxicity due to excessive intracellular Ca + 2 increase and neuron death by many mechanisms that trigger each other such as disruption in membrane cation channels are encountered [133, 134]. The amyloid-beta (Aβ) peptide triggers O2 radical production in endothelial cells and induces oxidative and peroxidative reactions, causing cell death. As an example of these reactions; the oxidative reaction catalysed by the combination of amyloid plaques with heavy metal ions and lipid membrane peroxidation by various mechanisms can be given. It has been observed that the increased ROS activity via Aβ in tissue taken from the hippocampus caused synaptic disruption and cell death as a result of increased Ca + 2 increase with N-methyl-D-aspartate (NMDA) channel activation. Besides, mitochondria dysfunction is an important point in AD pathology. In biopsy studies, it was found that mitochondria shrank and protein and DNA dispersed into the cytoplasm [135, 136].

One of the brain RAAS products, the Ang- (1–7) peptide is a Mas receptor [MASR] agonist [137]. MASRs are abundant in memory-related areas of the brain and accelerate hippocampal long-term potentiation (LTP) together with Ang- (1–7). Also, it is known that the neuroinflammatory effects of Ang II, another RAAS product, contribute to cognitive disorders. Reversing the biological effects of Ang II with the anti-inflammatory, anti-fibrotic, vasodilator and anti-proliferative biological effects of Ang- (1–7); supports memory and learning [138]. In brain tissue studies in AD, it has been shown that the expression and activity of ACE, the metabolic enzyme of Ang-II, changes significantly in certain regions of the brain, including the frontal cortex and hippocampus. It has been reported that when centrally acting ACE inhibitors are used, they have reduced cognitive decline and have memory-enhancing effects [139, 140]. ACE2 activity decreases in AD pathology [141]. Ang- (1–7) improves memory functions without affecting hippocampal or cortical amyloid peptide storage [142].

Ang II causes oxidative stress through the AT1 receptor [143] and increases superoxide. Thus, it causes neuroinflammation and vascular diseases [144]. As a result, it causes Aβ accumulation due to AD. However, the AT2 receptor signal produces beneficial effect including learning and memory. Angiotensin receptor blockers (ARBs) inhibit AT1R signalling, which shifts the effect of Ang-II towards the beneficial path (AT2R signal) (**Figure 5**) [144].

ACE inhibitors have a protective effect against AD. It shows this effect by suppressing brain-derived neurotrophic factor reduction and TNF-α release. *Role of the Renin-Angiotensin-Aldosterone System in Various Disease Processes: An Overview DOI: http://dx.doi.org/10.5772/intechopen.97354*

**Figure 5.**

*Effect of AngII on the nervous system. Amyloid plaque (A*β*), angiotensin II (AngII), angiotensin I (AngI), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), angiotensin (AT), AT2 receptor (AT2R), AT1 receptor (ATR1R).*

ACE inhibitors also improve oxidative-nitrosative stress and nitrotyrosine production, which reduces amyloidogenesis and subsequent Aβ accumulation [145, 146]. On the other hand, ACE inhibitor (Captopril) and Angiotensin receptor blockers (Telmisartan, Candesartan, Losartan) ameliorate oxidative stress [147–151]. Telmisartan normalises the decreased thioredoxin (TRX) system in addition to attenuating the expression of the protein (TXNIP) that interacts with thioredoxin. Thus, it reduces the formation of endogenous ROS [149]. Similarly, telmisartan reduces improved glycation end products and 4-hydroxynonenal, which are markers of oxidative stress and are associated with Neurodegeneration [150]. Candesartan lowers the level of free radicals in the brain by decreasing malondialdehyde and increasing glutathione levels [151].

#### **5.2 Parkinson's disease**

Ang II levels are high in the striatum and substantia nigra of Parkinson's disease (PD) patients. Ang II and AT1R trigger apoptosis by activating autophagy in a dopaminergic neuronal cell. These findings suggest that Ang II plays a role in the pathogenesis of PD [152]. In animal models of PD, it has been found that the signalling of AT2Rs is decreased with the loss of function in dopaminergic neurons [153]. Also, ACE and ACE2 were detected in the cerebrospinal fluid of PD patients. ACE levels are decreased in the cerebrospinal fluid of PD patients [154].

#### **5.3 Multiple sclerosis**

Multiple sclerosis (MS) is defined as an autoimmune neurodegenerative disease that typically occurs in the third or fourth decade of life [155]. Although the aetiology of the disease is not fully known, both environmental and genetic factors are

thought to play an important role in the development of MS [156]. Blocking angiotensin II production by ACE inhibitors and inhibition of angiotensin II signalling by AT1 receptor blockers suppresses T-helper 17 (Th17) cells [157]. Th17 cells play an important role in the development and relapse of MS [158]. In a study, ACE activity in the blood serum of MS patients was reported to be higher than in healthy controls [159]. In another study, ACE and ACE2 levels were found to be reduced in the cerebrospinal fluid of MS patients [160].

### **6. Conclusion**

As understood, the renin-angiotensin-aldosterone system plays a very important role in regulating the fluid-electrolyte balance and blood pressure in the body. RAAS has receptors in many organs and tissues and can show various effects here. RAAS can be affected by various diseases affecting the cardiovascular, renal, nervous and respiratory systems and plays a major role in the formation of damage that may occur in these systems. Drugs that can affect the components or receptors of RAAS can prevent damage that may occur. The presented study shows the importance of the role of this system in the mentioned diseases. Understanding the role of this system in the mentioned diseases is of great importance in the development of new treatment protocols and new therapeutic agents.

### **Author details**

Volkan Gelen1 \*, Abdulsamed Kükürt2 and Emin Şengül3

1 Department of Physiology, Faculty of Veterinary Medicine, Kafkas University, Kars, Turkey

2 Department of Biochemistry, Faculty of Veterinary Medicine, Kafkas University, Kars, Turkey

3 Department of Physiology, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey

\*Address all correspondence to: gelen\_volkan@hotmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Role of the Renin-Angiotensin-Aldosterone System in Various Disease Processes: An Overview DOI: http://dx.doi.org/10.5772/intechopen.97354*

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#### **Chapter 4**

## Renin Angiotensin Aldosterone System Functions in Renovascular Hypertension

*Jose A. Gomez*

#### **Abstract**

The renin angiotensin aldosterone system (RAAS) plays a key function in renovascular hypertension induced by renal artery stenosis (RAS). RAS causes a decrease in renal perfusion in the stenosed kidney which in turn stimulates renin the rate limiting enzyme in RAAS. This stimulation triggers a series of events starting with renin release leading to Ang II production, decrease in sodium excretion, increase sympathetic tone; all contributing to the development of renovascular hypertension. In RAS increase of superoxide reduce nitric oxide in the afferent arteriole increasing vasoconstriction and a marked decrease in glomerular filtration rate. In renovascular hypertension prostaglandins mediate renin release in the stenosed kidney. Targeting different RAAS components is part of the therapy for renovascular hypertension, with other options including renal nerves denervation and revascularization. Different clinical studies had explored revascularization, RAAS blocking and renal nerves denervation as a therapy. We will discuss organ, cellular and molecular components of this disease.

**Keywords:** Renin angiotensin aldosterone system, renovascular hypertension, renin, renal nerves, oxidative stress

#### **1. Introduction**

Renal artery stenosis (RAS) is a common condition in patients suffering from atherosclerosis and fibromuscular dysplasia [1–6], with an overall prevalence disease rate of 15.4% [4]. Progression to severe stenosis is well documented and leads to hypertension and kidney damage [7–9]. Clinically, renovascular hypertension is one the most important causes of secondary hypertension and kidney damage. In patients with RAS, 65% are hypertensive and 26.5% suffer kidney failure [4, 6]. Advancement to end stage renal disease is known to increase cardiovascular events [10]. The clinical trials Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) [11], and Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) [12] targeted renal vascularization to improve disease outcomes but failed to show any improvement in renal function, cardiovascular events or mortality [11, 12]. Furthermore, prospective studies in ASTRAL and CORAL concluded that 15-22% of patients suffering from renovascular disease will progress to renal "end point" within 3 to 4 years [13]. The NHLBI Cardiovascular Health Study used a non-invasive screen and found that 6.8% elderly patients (both African American

#### **Figure 1.**

*Renin Angiotensin Aldosterone System (RAAS) key role in renal artery stenosis (RAS) induction of renovascular hypertension and kidney damage. Deterioration of renal perfusion in the stenosed kidney cause a decrease in renal pressure which in turn stimulates RAAS. This stimulation triggers a series of events starting with renin release leading to angiotensin II production; decrease in sodium excretion, increase sympathetic tone; ending in hypertension.*

and white) had more than 60% RASten or renal artery occlusion [14, 15]. The renin angiotensin aldosterone system (RAAS) plays a key role in hypertension, with renin recognized as the driver of renovascular hypertension (**Figure 1**). In humans, plasma renin activity (PRA) is used as biomarker for the activation of RAAS in hypertension and in patients with atherosclerotic RAS, high PRA is associated with increased risk for cardiovascular events and high mortality [16]. These suggest an important function for RAAS in renovascular hypertension onset and the need to target different components of RAAS for therapy.

#### **2. Renin angiotensin aldosterone system function in renal artery stenosis**

Renal artery stenosis causes a decrease in renal perfusion in the stenosed kidney which in turn stimulates RAAS. This stimulation triggers a series of events starting with renin release leading to angiotensin II (Ang II) production, decrease in sodium excretion, increase sympathetic tone; all contributing to the development of hypertension (**Figure 1**) [17, 18]. When there is a need for renin expression and release, the number of renin expressing cells increase a process known as Juxtaglomerular (JG) cell recruitment [19–24] involving the trans differentiation of vascular smooth muscle cells into renin expressing cells along the afferent arteriole [20, 21, 23]. JG cell recruitment is well documented in this model [25–27]. Activation of the renal baroreceptor in RAS causes renovascular hypertension through RAAS activation [28]. In uni- and bi-lateral RAS aldosterone levels are upregulated [29–32]. Moreover, in renovascular hypertension prostaglandins mediate renin release in the stenosed kidney [33–36], and catecholamines mediated by an increase in cAMP and activation of protein kinase A (PKA) [37–39]. Decrease renal perfusion cause a decline in renal function and increase kidney injury [40, 41]. This decrease in renal function starts with endothelial damage, decrease in nitric oxide and increase in vasoconstrictors and oxidative species [42]. Reactive oxidative stress (ROS) increase renal vascular tone, tubuloglomerular feedback, and endothelial disfunction decreasing glomerular filtration rate [43].

Successful treatments for hypertension such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) alleviate hypertension,

#### *Renin Angiotensin Aldosterone System Functions in Renovascular Hypertension DOI: http://dx.doi.org/10.5772/intechopen.97491*

but need close examining for kidney failure and hyperkalemia [4]. Aliskiren, a direct renin inhibitor, may still be a potential option for the treatment of high blood pressure in some forms of hypertension such as chronic kidney disease (CKD) and renovascular hypertension [44]. In a clinical study, aliskiren combined with olmesartan reduced proteinuria by about 40% from baseline in patients with CKD with persistent proteinuria [45]. In non-diabetic CKD patients, aliskiren combined with ARBs, safely reduced proteinuria and attenuated the decline in glomerular filtration rate (GFR) [46]. These results indicate that a complete treatment of renal artery stenosis induced renovascular hypertension and kidney damage may need targeting both the angiotensin II-dependent and the Ang II-independent arms of RAAS.

Renal artery stenosis is common in diabetic patients placing them at higher risk of end organ damage causing end stage renal disease [9, 47–49]. In older patients, RAS is the most common problem of end stage renal failure [50]. In RAS renin is recognized as the disease driver [6, 16, 51–54]. RAS is common in atherosclerotic patients and caused hypertension, oxidative stress, and kidney damage [7, 9]. Increased oxidative stress has been reported in humans as well as in two kidney one clip (2K1C) animal model and other hypertensive animal models [24, 55–60]. Changes in renal perfusion activate RAAS and increase the sympathetic activity of the afferent renal nerves contributing to renovascular hypertension and end-stage renal disease during RAS [61]. In the 2K1C model renal denervation decreases hypertension [62, 63]. Clinical trials (Renal Denervation in Patients With Refractory Hypertension (HTN-1) (Symplicity HTN-1), Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-2), The Renal Denervation for Hypertension (DENERHTN), and Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL)) report that using renal denervation as therapy for hypertension has good outcomes [64–67]. The therapeutic effects of renal denervation have been attributed to removal of sympathetic efferent and/or afferent fibers [68]. Renin secretion is stimulated by renal efferent nerves, which also stimulate tubular sodium reabsorption [62] without perturbations to glomerular filtration rate or albumin urinary secretion [69]. These indicates that initially, renal artery stenosis induces RAAS and in later stages other organs involved in blood pressure homeostasis are involved in the induction of renovascular hypertension such as renal nerves and adrenal gland.

#### **3. Central nervous system input in renal artery stenosis**

Different experimental models of hypertension showed the crucial role play by the central nervous system (CNS) in this disease. Specifically, sympathetic efferent outflow augments during hypertension. It has been shown that both Ang II and aldosterone actions are mediated by the CNS [70, 71]. In experimental models of hypertension, ablation of the forebrain surrounding the anteroventral third cerebral ventricle (AV3V) inhibited hypertension [72, 73]. In the CNS the AV3V contains the median preoptic eminence, the organum vasculosum of the lateral terminalis, and the preoptic periventricular nucleus [74]. This forebrain region is responsible for cardiovascular regulation, and includes the subfornical organ, the organum vasculosum of the lamina terminalis, which are circumventricular organs lacking a blood-brain barrier [75]. Production of ROS in these brain regions strongly influences blood pressure [76]. Several reports showed that actions on these brain regions are responsible for Ang II hypertension and increase oxidative stress with NADPH oxidase playing a key role [77–80]. Renal vasculature and tubular segments are controlled by the efferent sympathetic renal nerves and promote arteriolar

vasoconstriction and renin release and increases sodium reabsorption [81]. In the afferent arterioles Ang II activates the alpha1 adrenergic receptor, which increases oxidative stress and constriction of the afferent arterioles, reducing renal blood flow [82]. Contrary, activation of the b1-adrenergic receptor activation inhibits ROS generation promoting vasodilation [83]. In different hypertension animal models renal denervation inhibit the induction of hypertension, showing that ablation of renal efferent induction of ROS is important in hypertension development [84, 85]. These data indicate that oxidative stress control efferent and afferent renal nerve actions in the development of hypertension.

Renal artery stenosis activates RAAS and increases the activity of the afferent renal nerves resulting in hypertension and end-stage renal disease [61]. It is known that in the 2K1C model renal denervation decreases hypertension [62, 63]. Removal of sympathetic efferent and/or afferent fibers controls hypertension [68], and the renal efferent nerves stimulate renin secretion and tubular sodium reabsorption [62]. During renal artery stenosis, there is an increase in Neutrophil Oxidase Factor p47 (p47phox) and p67phox [86–88]. Furthermore, in renal artery stenosis generation of ROS induced renal damage [88, 89], with the main source of ROS being NADPH oxidase [90, 91].

In the induction of renovascular hypertension, the renal nerves as well as the renin angiotensin aldosterone system activation cause the increase in blood pressure and dysregulation of sodium secretion, with renal denervation alleviating the central nerve system input decreasing blood pressure.

#### **4. Oxidative stress in renal artery stenosis**

Oxidative stress in the kidney and vasculature contribute to hypertension development. NADPH oxidase is a major source of oxidative stress in mammalian cells [75]. Most of the renal cells express NADPH oxidase and there are several stimuli that cause its activation leading to organ injury and hypertension development [75, 92, 93]. Reactive oxygen species (ROS) produced by NADPH oxidase in the kidney cause vasoconstriction and organ injury. Specifically, increase of superoxide reduces nitric oxide (NO) in the afferent arteriole increasing vasoconstriction and a marked decrease in GFR. In rabbits, Ang II-induced hypertension increase the p22phox subunit of NADPH oxidase causing endothelial dysfunction in the afferent arteriole [94]. Moreover, in spontaneous hypertensive rats, superoxide is generated in the afferent arteriole in response to endothelin-1 (ET-1) [95, 96]. Podocytes are important components of the renal filtration system. Dahl salt-sensitive rats had increase glomerular expression of p22phos and NOX2 that increases oxidative stress causing podocyte injury, glomerular sclerosis and proteinuria, with the antioxidant tempol (4-Hydroxy-TEMPO) correcting this glomerular injury [97, 98]. Plasminogen causes podocyte injury through stimulation of NOX2 and NOX4 expression [99], Ang II stimulates ROS generation in the mitochondria stimulating autophagy [100], Ang II-induced ROS production caused glomerulosclerosis [101], and oxidative stress disrupts nephrin – caveolin-1 crosstalk in podocytes disrupting of glomerular filtration barrier [102]. In the vasculature, increased oxidative stress causes hypertension in different animal models [103–108]. During renal artery stenosis, generation of ROS is recognized as the main mechanism of renal damage [88, 89, 109, 110] with the activation of NADPH oxidase as the source of ROS [90, 91], and associated with an increase in p47phox and p67phox [19, 86–88].

It is important to recognize that renal artery stenosis increase the production of reactive oxygen species leading to renal damage. ROS production influences not only organ damage but also contributes to the increase in blood pressure.

In the therapy of this disease multiple molecules are involved leading to increases in oxidative stress, blood pressure and renal injury and all start with the activation of the renin angiotensin aldosterone system.

#### **5. Angiotensin II dependent and independent action in renal artery stenosis**

In renal artery stenosis induction of renovascular hypertension, renin is recognized a key molecule, and as such in the therapy of renovascular hypertension Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor blockers (ARBs) are used [4]. Moreover, sympathetic nervous systems action in the kidney promotes renin secretion through renal efferent nerves, which also stimulate tubular sodium reabsorption [62], and in the 2K1C model denervation inhibit the onset of hypertension [62, 63]. Renal artery stenosis causes renovascular hypertension, which is associated with deterioration of kidney function [20]. Reduction in renal flow is recognize as a source of hypoxia during renovascular hypertension [21]. Arterial stenosis causes thrombosis, and ischemia in renovascular hypertension [22]. During renal artery stenosis generation of ROS is recognized as the main mechanism of renal damage [88, 89], causing increased in vasoconstrictors, cell death and decrease in the activity of nitric oxide [109, 110]. A swine model of renal artery stenosis presented an increase in ROS, renal and cardiac damage [23, 86–89, 111–113]. In renal artery stenosis activation of RAAS increase ROS generating by the activation of NADPH oxidase [90, 91], associated with is an increase in p47phox and p67phox [86–88]. Phosphorylation of p47phox by PKC is a key step in NADPH oxidase activation [114–118]. Hypertension is associated with PKC activation and increase oxidative stress [119], which caused endothelial nitric oxide synthase (eNOS) disfunction and uncoupling producing ROS instead of NO. This uncoupling is a key mechanism for endothelial dysfunction in angiotensin II-induced hypertension [120–122]. Increase in NOX2 activity requires increase NOX2 expression and p47phox association and activation of NOX2 [19]. Furthermore, increase in oxidative stress is well documented in 2K1C model [55–59, 123, 124]. All the actions mentioned above are Ang II mediated.

New evidence places (pro)renin receptor (PRR) as an effector molecule in the Ang II-independent RAAS [125]. PRR binds both renin and prorenin [125–129]. There is an association of PRR with different pathophysiology of diseases [130–135]. PRR binds renin causing an increase in Ang I [125] and it can activate prorenin by promoting a conformational change [125–129]. PRR mRNA is expressed in different organs such as kidney, heart, brain, eye, adipose tissue and vascular SMCs [125, 134], It has been proposed that PRR activates the Ang II-independent RAAS with tissue specificity [136]. My laboratory and others are uncovering new functions of the Ang II independent pathway in blood pressure, oxidative stress and organ damage. New studies will define the relevance of this arm of RAAS and possible define new molecular targets for therapy.

#### **6. Concluding remarks and future perspectives**

In the definition of the molecular pathways involved in the development of renovascular hypertension, the Goldblatt two kidney one clip animal model has been critical. This animal mode has been extensively used with different animals all showing that renal artery stenosis strongly stimulates renin overexpression and release promoting renovascular hypertensions and kidney injury. In renovascular

hypertension renin is key and promotes the increase in Ang II leading to hypertension. Renin being the rate limiting step in the production of Ang II in RAAS, has been investigated as a possible target for the therapy. However, the main therapies used are angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Direct renin inhibition by aliskiren, is potential therapy for hypertension in chronic kidney disease (CKD) and renovascular hypertension. Combination of aliskiren with olmesartan in the clinic, reduced proteinuria in patients with CKD with persistent proteinuria. In non-diabetic CKD patients, aliskiren combined with ARBs, reduced proteinuria and protected from the decline in glomerular filtration rate. We have shown here clinical and research data that indicates the during renal artery stenosis induced renovascular hypertension RAAS is activated and play a critical role in this pathology. It is important that a complete treatment of renovascular hypertension may need targeting both the angiotensin II-dependent and the Ang II-independent arms of RAAS.

### **Acknowledgements**

We apologize to colleagues whose work has not been included in this chapter due to space limitations. This work was supported by NIH Grants: NHLBI Research Scientist Development Grant (1K01HL135461).

### **Author details**

Jose A. Gomez Department of Medicine, Clinical Pharmacology Division, Vanderbilt University Medical Center, Nashville, TN, United States

\*Address all correspondence to: jose.a.gomez@vumc.org

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Renin Angiotensin Aldosterone System Functions in Renovascular Hypertension DOI: http://dx.doi.org/10.5772/intechopen.97491*

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[133] Ichihara A, Sakoda M, Kurauchi-Mito A, Kaneshiro Y, Itoh H. Renin, prorenin and the kidney: a new chapter in an old saga. J Nephrol 2009;22:306-11.

[134] Ichihara A, Sakoda M, Mito-Kurauchi A, Itoh H. Activated prorenin as a therapeutic target for diabetic nephropathy. Diabetes Res Clin Pract 2008;82 Suppl 1:S63-6.

[135] Kaneshiro Y, Ichihara A, Sakoda M et al. Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. J Am Soc Nephrol 2007;18:1789-95.

[136] Nabi AH, Suzuki F. Biochemical properties of renin and prorenin binding to the (pro)renin receptor. Hypertens Res 2010;33:91-7.

#### **Chapter 5**

## The Role of Renin Angiotensin Aldosterone System in the Progression of Cognitive Dysfunction in Chronic Kidney Disease Patients with Alzheimer's Disease

*Vinothkumar Ganesan*

### **Abstract**

Renin angiotensin aldosterone (RAAS) is very well established as a regulator of blood pressure (BP) and a determinant of target organ injury. It controls fluid and electrolyte balance through coordinated effects on the heart, blood vessels, and kidneys. The main effector of RAAS is angiotensin II (Ang II), which exerts its vasoconstrictor effect primarily on the postglomerular arterioles, thereby raising the glomerular hydraulic pressure and ultrafiltration of plasma proteins, which may lead to the initiation and progression of chronic kidney disease (CKD). RAAS also plays a, key role in hypertension and cerebrovascular disease. Enhanced Ang II levels accelerate the initiation and progression of cell senescence by fostering inflammation and oxidative stress. Sustained activation of RAAS facilitates agingrelated CKD and results in cognitive dysfunction and Alzheimer's disease (AD). However, in many hypertension treatment studies, the frequency of fatal and nonfatal stroke has been greatly reduced, and this is very important since a history of stroke doubles the risk of dementia in both patients without CKD and hemodialysis. In CKD patients with AD, anemia has also been identified as a risk factor for cognitive impairment, and correction of anemia with recombinant erythropoietin treatment has been shown to enhance cognition measures, such as AD markers and neuropsychological tests.

**Keywords:** Angiotensin converting enzyme, Chronic Kidney Disease, Cognitive Dysfunction, Alzheimer's disease, Amyloid β, Tau

#### **1. Introduction**

The renin angiotensin aldosterone (RAAS) system is a hormone system in the body that is responsible for controlling the balance of fluid and blood pressure. The system consists primarily of three hormones, namely renin, angiotensin II and aldosterone. It is controlled mainly by the rate of renal blood flow. The main effector of RAAS is angiotensin II (Ang II), Rising glomerular hydraulic pressure and ultra-filtration of plasma proteins, which can contribute to the initiation and progression of chronic kidney disease (CKD), as well as key molecules in hypertension and cerebrovascular disease, exerts its vasoconstrictor effect primarily on postglomerular arterioles. Enhanced Ang II levels speed up the initiation and progression of cell senescence by encouraging inflammation and oxidative stress. Sustained RAAS activation facilitates aging-related CKD and results in cognitive decline and Alzheimer's disease (AD). The risk of cognitive dysfunction in CKD patients with AD is significantly greater than in patients without CKD [1], not only in aged patients with CKD, but also in young patients with CKD [2]. It has been believed for a long time that kidney function is associated with brain activity. Our recent clinical studies indicate that CKD patients are more vulnerable to cognitive dysfunction and AD, and the severity of cognitive dysfunction is closely linked to the development of CKD and kidney failure [3–5].

### **2. RAAS: pathogenic mechanism of chronic kidney disease**

RAAS is the best known blood pressure regulator (BP) and the determinant of hypertension damage to the target organs. It also regulates the balance of fluids and electrolytes by coordinated impacts on the heart, blood vessels, and kidneys. The main effector of the RAAS is Ang II [6]. Renin is secreted from the juxtaglomerular apparatus of the kidney in the classic RAAS pathway and acts on the circulating precursor angiotensinogen to create angiotensin I. Angiotensin I has few effects on BP, and in the lungs, ACE is transformed to Ang II. Ang II operates on the heart and kidneys by binding to type 1 (AT1) and type 2 (AT2) G-protein coupled receptors [7]. The more deleterious effects of Ang II, vasoconstriction and heart and vessel hypertrophy are mediated by the AT1 receptor. In addition the vasodilator peptide bradykininin is inactivated by the angiotensin-converting enzyme (ACE)

**Figure 1.**

*The pathogenic mechanism of chronic kidney disease in the renin angiotensin aldosterone system.*

*The Role of Renin Angiotensin Aldosterone System in the Progression of Cognitive Dysfunction… DOI: http://dx.doi.org/10.5772/intechopen.96048*

in addition to the conversion of angiotensin I to Ang II [7]. Recently, ACE type 2 (ACE2) has been found to cleave angiotensin I into inactive angiotensin1–9, transformed by ACE into vasodilator and antiproliferative angiotensin1–7, respectively [8, 9]. While ACE2 in the human kidney is known to be present, there was no evidence on the distribution of tissues in kidney disease [8]. Kidney biopsies from patients with different kidney disorders, including transplant patients, were studied in a recent review. ACE2 was present in the tubular and glomerular epithelium and in the vascular smooth muscle cells and the interlobular artery endothelium in the control kidneys [10]. Neo-expression of ACE2 has been observed in the glomerular and peritubular capillary endothelium in all kidney diseases. Treatment with ACE inhibitors did not change ACE2 expression [10]. In vivo, Ang II increases the vascular tone of both afferent and efferent glomerular arterioles and modulates capillary intraglomerular pressure and glomerular filtration rate (GFR). Ang II primarily exerts its vasoconstrictor effect on the postglomerular arterioles, thereby raising the glomerular hydraulic pressure and filtration fraction, and impairing the glomerular barrier's selective size role for macromolecules, such as plasma proteins [11]. Intra capillary hypertension and increased plasma protein ultrafiltration can lead to the onset and progression of CKD [12]. Angiotensin non-hemodynamic effect may also be relevant in the progression of kidney disease [6].

A diagrammatic sketch of the pathogenic role of RAAS in chronic kidney disease is shown in **Figure 1**.

#### **3. RAAS: pathogenic mechanism of Alzheimer's disease**

Alzheimer disease (AD) is the most common neurodegenerative disease associated with dementia in the elderly. Various mechanisms, including DNA damage, lysosomal dysfunction, epigenetic modulation, and immune dysregulation, have been involved in neurodegenerative pathogenesis. Importantly, the homeostasis between protein synthesis, folding, and clearance of unfolded proteins, called proteostasis, is disrupted in AD and other neurodegenerative diseases. This contributes to an accumulation of proteins that are oligomerized and aggregated (Intracellular Tau (Neurofibrillary tangles [NFT]), and extracellular amyloid β (Aβ) (Senile plaques)) that ultimately induce protein toxicity. In many neurodegenerative disorders, including AD, oxidative stress are frequently found. In AD, Aβ accumulation, tau hyperphosphorylation, and the resulting degradation of synapses and neurons may be promoted by oxidative stress. In several target cells, Ang II has been shown to induce mitochondrial dysfunction through angiotensin II type 1 receptor (AT1R). Mechanistically, Ang II increases mitochondrial reactive oxygen species (ROS) [13]. Several studies indicate that ROS is involved in the development of Aβ fibrillation and NFT in AD and increases the pathology of Aβ and NFT in AD [14, 15].

The hyperactivity of the RAAS classical axis, mediated by AT1R, is implicated in the pathogenesis of AD. Ang II intracerebroventricular infusion increased both of the amyloid-β (Aβ) [16] and tau pathology, and also reduced cognitive performance [17], in aged normal rats. In most but not all AD mouse models, angiotensin II type 1 receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) minimize the amount of AD-like pathology and increase cognitive efficiency [18, 19]. Clinical studies have also identified ACE2 and ACE as brain RAAS factors, not only in the regulation of blood pressure, but also in the conversion of Aβ43 to Aβ40, which may decrease Aβ accumulation associated with AD and decrease serum ACE-2 activity in AD patients compared to control subjects [20].

A diagrammatic sketch of the pathogenic role of RAAS in Alzheimer's disease is shown in **Figure 2**.

**Figure 2.**

*Pathogenic Alzheimer's disease pathway of the renin angiotensin aldosterone system.*

#### **4. Hypertension is a risk factor for cognitive dysfunction in chronic kidney disease patients with Alzheimer's disease**

The most common neurodegenerative disorders associated with CKD in the elderly are AD and dementia. Ang II represents a central molecule in cerebrovascular pathology and hypertension. Enhanced Ang II levels speed up the initiation and progression of cell senescence by encouraging inflammation and oxidative stress. Sustained RAAS activation causes aging related end stage organ damage and results in cognitive decline and dementia [21]. Studies also show that hypertension is the most important factor that adversely affects cerebral aging modalities and is related to cognitive compromise in people who are aging [22, 23]. This discovery has contributed to the belief that hypertension, up to the point of AD and dementia, is one of the factors responsible for the compromise of cognitive function in the elderly. It is therefore hypothesized that aging contributes to systemic and tissue RAAS hyperactivity and a rise in neurogenic hypertension, whereas evidence that connects brain RAAS with AD, memory, and learning develops cognitive functions [24]. In this regard, one of the long-term hypertension complications is clinically defined as dementia (for example AD) or vascular dementia, associated with diseases of the degenerative central nervous system (CNS). The temporal association between dementia and broad cerebrovascular pathology indicates that there is a pattern of sudden initiation and progressive development of cognitive impairment in the onset of dementia within three months of the diagnosis of stroke. It is understood that hypertension raises the risks of the target organ, such as cardiomegaly, progressive hypertensive retinopathy, nephropathy and stroke. In addition to repeated episodes of stroke or acute ischemic attacks, chronic hypertension, which results in a reduction in cerebral blood flow, is associated with vascular dementia and results in cognitive impairment [25].

A diagrammatic sketch of the role of RAAS in the induction and mediation of high blood pressure and cognitive impairment in CKD patients with AD is shown in **Figure 3**.

*The Role of Renin Angiotensin Aldosterone System in the Progression of Cognitive Dysfunction… DOI: http://dx.doi.org/10.5772/intechopen.96048*

**Figure 3.**

*Chronic kidney disease and alzheimer's associated renin angiotensin aldosterone system share ageing related molecular pathways, including processing of APP, tau phosphorylation, and increased oxidative stress.*

#### **5. Treatment of cognitive dysfunction in chronic kidney disease patients with Alzheimer's disease**

Cognitive dysfunction is common among patients with CKD and dialysis in the memory, attention, and executive function domains. In our previous study, working memory and executive control, two main areas of cognitive ability, are potentially significant variables in drug compliance [4, 5]. Increased risk for injury, increased health care costs and progression to dementia are also associated with cognitive dysfunction without dementia [26]. Dementia is described by a drop in cognitive performance from a previous higher level along with a behavioral disorder that interferes with everyday function and independence. The brain and kidney vascular beds have identical anatomical and hemodynamic characteristics; these results have contributed to the speculation that cognitive dysfunction and CKD are a reflection of vascular damage in multiple end organs [26]. In addition, most patients with CKD have elevated rates of hypertension, diabetes, high levels of inflammatory receptors and vascular endothelial dysfunction, cardiovascular events like stroke, and carotid atherosclerosis, both leading to vascular cognitive decline and neurodegenerative diseases such as AD [27]. Potential steps to minimize cognitive impairment in CKD patients may include the treatment of cardiovascular risk factors, but, unfortunately, no clinical trials have been performed in CKD patients assessing cardiovascular risk factors for the prevention of cerebrovascular disease or cognitive impairment.

There is a trial showing that treatment with hypertension has a beneficial effect on cognition. In that survey, High blood pressure care with medication not only improves the cardiovascular health of older people, but can also reduce their risk of dementia and AD [27, 28]. The combined risk ratio of dementia preferred care in a meta-analysis of antihypertensive trials [29]. There is no strong evidence from

the trials in a systematic analysis of hypertension research to confirm that decreasing blood pressure prevents the development of dementia or cognitive decline in hypertensive patients with no clear previous CVD [30]. However, the occurrence of fatal and non-fatal stroke has been greatly decreased in many studies of hypertension treatment, and it is very important since a history of stroke doubles the risk of dementia in both patients with non CKD and *hemodialysis*. In CKD patients, Anemia has also been identified as a risk factor for cognitive decline in CKD patients, and our studies have shown correction of anemia with recombinant erythropoietin therapy to improve cognitive measures, such as AD markers and neuropsychological tests [4, 5].

#### **6. Future directions and challenges**

This chapter explores the relationship between RAAS, cognitive dysfunction anemic CKD patients and EPO. We then hypothesized that the EPO may inhibit ACE2 interest and likely eventually alter complicated signaling cascades to boost cognition through changes in AD markers. A main aspect of this assessment is that in anemic CKD sufferers with cognitive impairment, the limited molecular effects of the treatment with EPO are crystal-clear. I may conclude by saying that a bright future for the EPO remedy. In order to better understand the mechanisms underlying the effects of EPO in anemic CKD with AD patients, further research into pharmacogenomics and clinical trials is required.

### **Author details**

Vinothkumar Ganesan

Department of Medical Research, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, Kattankulathur, India

\*Address all correspondence to: vinothkumarbiochem@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*The Role of Renin Angiotensin Aldosterone System in the Progression of Cognitive Dysfunction… DOI: http://dx.doi.org/10.5772/intechopen.96048*

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[2] Hailpern SM, Melamed ML, Cohen HW, Hostetter TH. Moderate chronic kidney disease and cognitive function in adults 20 to 59 years of age: Third National Health and Nutrition Examination Survey (NHANES III). Journal of the American Society of Nephrology. 2007; 1;18 (7):2205-13.

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[4] Vinothkumar G, Krishnakumar S, Shivashekar G, Sreedhar S, Dinesh S, Sundaram A, Balakrishnan D, Riya VP. Therapeutic impact of rHuEPO on abnormal platelet APP, BACE 1, presenilin 1, ADAM 10 and Aß expressions in chronic kidney disease patients with cognitive dysfunction like Alzheimer's disease: a pilot study. Biomed Pharmacother. 2018; 104:211-222

[5] Vinothkumar G, Krishnakumar S, Riya VP. Correlation between abnormal GSK3ß, ß amyloid, total tau, p-tau 181 levels and neuro psychological assessment total scores in CKD patients with cognitivdysfunction: impact of rHuEPO therapy. J Clin Neurosci. 2019; 69:38-42.

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[8] Boehm M, Nabel EG: Angiotensinconverting enzyme 2—A new cardiac regulator. N Engl J Med 347:1795-1797, 2002

[9] Donoghue M, Hsieh F, Baronas E, et al: A novel angiotensinconverting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin. 2000; 1-9. Circ Res 87:E1–E9, Lely AT, Hamming I, Van Goor H, et al: Renal ACE2 expression in human kidney disease. J Pathol. 2004; 204:587-593

[10] Lely AT, Hamming I, Van Goor H, et al: Renal ACE2 expression in human kidney disease. J Pathol.2004; 204:587-593

[11] Yoshioka T, Rennke HG, Salant DJ, et al: Role of abnormally high transmural pressure in the permselectivity defect of glomerular capillary wall:Astudy in early passive Heymann nephritis. Circ Res.1987; 61:531-538

[12] Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med.1998; 339:1448-1456

[13] Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, Scalia R, Eguchi S. Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology. Physiol Rev. 2018;98:1627-1738.

[14] Martínez E., Navarro A., Ordóñez C., del Valle E., Tolivia J. Oxidative stress induces apolipoprotein D overexpression in hippocampus during aging and alzheimer's disease. Journal of Alzheimer's Disease. 2013;36(1):129-144.

[15] Zhao Y., Zhao B. Oxidative stress and the pathogenesis of alzheimer's disease. Oxidative Medicine and Cellular Longevity. 2013;2013:10.

[16] Zhu D, Shi J, Zhang Y, Wang B, Liu W, Chen Z, et al. Central angiotensin II stimulation promotes β amyloid production in Sprague Dawley rats. PLoS One. 2011;6:e16037.

[17] Tian M, Zhu D, Xie W, Shi J. Central angiotensin II-induced Alzheimer-like tau phosphorylation in normal rat brains. FEBS Lett. 2012;586:3737-3745.

[18] Dong YF, Kataoka K, Tokutomi Y, Nako H, Nakamura T, Toyama K, et al. Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer's disease. FASEB J. 2011;25:2911-2920.

[19] Ongali B, Nicolakakis N, Tong XK, Aboulkassim T, Papadopoulos P, Rosa-Neto P, et al. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model. Neurobiol Dis. 2014;68:126-136.

[20] Liu S, Liu J, Miura Y, Tanabe C, Maeda T, Terayama Y, et al. Conversion of Aβ43 to Aβ40 by the successive action of angiotensin-converting enzyme 2 and angiotensin-converting enzyme. J Neurosci Res. 2014;92:1178-1186.

[21] Bodiga VL, Bodiga S. Renin angiotensin system in cognitive function and dementia. Asian journal of Neuroscience. 2013

[22] Phillips S and Whisnant J. "Hypertension and stroke," in Hypertension: Pathophysiology, Diagnosis, and Management, J. Laragh and B. Brenner, Eds, Raven Press, New York, NY, USA, 2nd edition, 1990; 417-431

[23] Strandgaard S, Paulson OB. Cerebrovascular consequences of hypertension. The Lancet. 1994 Aug 20;344(8921):519-521

[24] Phillips MI and De Oliveira EM. "Brain renin angiotensin in disease," Journal of Molecular Medicine, 2008;86; 6;715-722

[25] Andel R, Hughes TF, and Crowe M, "Strategies to reduce the risk of cognitive decline and dementia," Aging Health, 2005;1, 107-116

[26] Tamura MK, Yaffe K. Dementia and cognitive impairment in ESRD: diagnostic and therapeutic strategies. Kidney international. 2011;1;79(1):14-22.

[27] Langa KM, Foster NL, Larson EB. Mixed dementia: emerging concepts and therapeutic implications. 2004; 15; 292(23):2901-8.

[28] Williamson, JD, Miller, ME, Bryan, RN, Lazar, RM, Coker, LH, Johnson, J, Cukierman, T, Horowitz, KR, Murray, A, Launer, LJ. "The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Study (ACCORD-MIND): rationale, design, and methods". Am J Cardiol. 2007; 99 112i-122i

[29] Ding J, Davis-Plourde KL, Sedaghat S, Tully PJ, Wang W, Phillips C, Pase MP, Himali JJ, Windham BG, Griswold M, Gottesman R. Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective

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cohort studies. The Lancet Neurology. 2020; 1;19(1):61-70

[30] Sofi, F, Valecchi, D, Bacci, D, Abbate, R, Gensini, GF, Casini, A, Macchi, C. "Physical activity and risk of cognitive decline: a meta-analysis of prospective studies". J Intern Med. 2011; 269,107-117.

#### **Chapter 6**

## Renin Angiotensin Aldosterone System, Glucose Homeostasis, and Prevention of Type 2 Diabetes: Mechanistic Insights and Evidence from Major Clinical Trials

*Samara Skwiersky, Sandra Iwuala, Seeta Chillumuntala, Deborah Osafehinti and Jocelyne Karam*

#### **Abstract**

With its alarmingly rising prevalence worldwide, type 2 diabetes has become a leading cause of morbidity and mortality around the planet. Efforts to prevent progression to diabetes in individuals at risk could have a significant positive public health impact. Multiple trials examining cardiovascular outcomes of Renin-Angiotensin-Aldosterone System (RAAS) inhibitors revealed, in secondary analysis, a significantly reduced risk of new onset diabetes in participants receiving these agents. This glycemic protective effect is attributed to the known implication of RAAS in the development of insulin resistance and type 2 diabetes. The DREAM trial and the NAVIGATOR trial were two large randomized controlled studies examining, as primary outcome, the effect of Ramipril and Valsartan respectively on the incidence of diabetes in patients with prediabetes. Their results confirmed a favorable glycemic effect of RAAS inhibition agents and suggested a possible added benefit of diabetes prevention to their other several cardiovascular and blood pressure benefits.

**Keywords:** diabetes prevention, renin-angiotensin- aldosterone system, glucose homeostasis, ACE inhibitors, angiotensin receptor blockers, prediabetes

#### **1. Introduction**

Diabetes Mellitus (DM) is a chronic disease characterized by hyperglycemia due to impaired glucose regulation [1]. Glucose regulation is controlled by insulin, a protein hormone produced and secreted by the -cells of the pancreas. Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and impaired -cell function, eventually leading to decreased insulin secretion.

Prediabetes is the disease state which precedes the diagnosis of diabetes [2]. It is characterized by hyperglycemia caused by insulin resistance and -cell dysfunction, as is type 2 diabetes, but before serum glucose levels reach that of diabetic diagnostic thresholds. Just as in diabetes, the diagnosis of prediabetes is made based on results of fasting plasma glucose, oral glucose tolerance test, Hemoglobin A1c, and/or random serum glucose levels [3]. Prediabetes can be defined by impaired fasting

glucose (IFG) with a fasting plasma glucose level 100–126 mg/dL (5.5–7.0 mmol/L), impaired glucose tolerance (IGT) with glucose level of 140–200 mg/dL (7.8–11.1 mmol/L) at 2 hours of the oral glucose tolerance test (OGTT), and/or HbA1c level of 5.7–6.5% (39–48 mmol/mol) [2, 3].

As the prevalence of diabetes continues to increase, it has become a severe public health problem worldwide. According to the World Health Organization (WHO) and International Diabetes Foundation (IDF), 451 million adults were diagnosed with diabetes worldwide in 2017, which was drastically increased from 108 million in 1980 [2–4]. This number is expected to increase to 693 million by the year 2045 [3]. According to the CDC, in 2015, approximately half (48.3%) of the adult population ages 65 and older had prediabetes [2].

With its many microvascular and macrovascular complications, diabetes contributes to a large portion of healthcare costs worldwide. In fact, approximately 850 billion USD of the global healthcare expenditure was spent on patients with diabetes in 2017 [2]. Research has shown that individuals with diabetes are at increased risk of cardiovascular disease (CVD), the leading cause of death worldwide [1]. The Framingham Heart study found that women with diabetes had a five times greater risk of heart failure, while men had two times greater risk, when compared to individuals of the same age and gender without diabetes [5]. Prediabetes has also been found to be independently associated with microvascular complications, macrovascular complications (including CVD) and increased risk of overall mortality [6, 7].

Aside from the increased risk of CVD in individuals with diabetes, an independent association between hypertension and insulin resistance has been established [8]. The Hong Kong Cardiovascular Risk Factor Prevalence Study found that of individuals with diabetes, 58% had elevated blood pressure, and of people with hypertension, 34% had impaired glucose tolerance. Only 42% of subjects studied with diabetes had normal blood pressure [9]. While the mechanism of this relationship is unclear, it has been hypothesized that patients with hypertension have impaired glucose tolerance due to changes in skeletal muscle tissue [10]. This common coexistence of hypertension and diabetes increases one's risk of CVD and events, and thus contributes to the increased risk of morbidity and mortality in these patients. Both hypertension and insulin resistance are components of the cardiometabolic syndrome, a group of interrelated abnormalities, which increase the risk for CVD and T2DM. Other related abnormalities include obesity, left ventricular hypertrophy, dyslipidemia, and albuminuria [10, 11].

Given the increasing prevalence of diabetes worldwide and its many complications, a significant effort has been made to explore preventive modalities. Studies have concluded that lifestyle interventions involving diet and physical activity reduce the risk of diabetes by greater than 50% [12]. However, the intense lifestyle modifications necessary to result in change are often difficult to implement. Bariatric surgery has been found to be an effective method of diabetes prevention and treatment. In a meta-analysis of 22,094 patients who had undergone bariatric surgery, diabetes was completely resolved in 76.8% of patients [13]. The Swedish Obese Subject Study, a prospective study of 4047 patients without diabetes who underwent gastric surgery, found that after 15 years, 392 of 1658 control patients developed diabetes compared to 110 of 1771 patients who underwent bariatric surgery (p < 0.001) [14]. Pharmacological agents such as metformin, thiazolidinediones, alpha-glucosidase inhibitors, and the glucagon-like peptide-1 agonist, liraglutide have been shown to prevent diabetes in those at risk [1, 15]. However, none of these agents have the added benefit of hypertension or CVD prevention and/or treatment. In fact, thiazolidinediones have been associated with an increased risk of congestive heart failure [12].

Pharmacological agents which act by inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) including Angiotensin-converting enzyme inhibitors


*Renin Angiotensin Aldosterone System, Glucose Homeostasis, and Prevention of Type 2... DOI: http://dx.doi.org/10.5772/intechopen.97737*

> **Table 1.** *Trials with diabetes prevention as a primary and secondary outcome of RAAS inhibition.*

(ACE-I) and angiotensin receptor blockers (ARBs) have been observed to have a favorable glycemic effect, and are among candidates examined in recent diabetes prevention trials. While they are often utilized for their blood pressure-lowering effect, they have cardiovascular benefits as well. Specifically, ACE-I have been found to play a role in the reversal of left ventricular hypertrophy in patients with hypertension, and preventing left ventricular remodeling post myocardial infarction [16]. Thus, ACE-I are indicated as first line agents in patients with heart failure, left ventricular systolic dysfunction (LVEF < 40–45%) and those with acute coronary syndrome and after suffering from an acute myocardial infarction [16]. In patients with heart failure, ACE-I have been shown to reduce mortality, hospitalizations, and prevent worsening of heart failure in these individuals [16]. The benefits of ARBs are less well defined, however, the clinical trial Val-HeFT found treatment with ARB, valsartan, resulted in decreased morbidity and mortality in patients with heart failure, when compared with placebo [17]. Additionally, ARBs have been found to slow the progression of diabetic nephropathy thus preventing end stage renal disease (ESRD) in these patients. Two trials, IDNT and RENAAL conducted in 2001, revealed ARBs (Irbesartan and Losartan) to be effective in reducing proteinuria and slowing the progression of ESRD in patients with diabetic nephropathy, independent of their blood-pressure lowering effect [18, 19].

Given these benefits, RAAS inhibitors are often first line agents for treating patients with concomitant hypertension and diabetes and those at risk for CVD. Several studies to date suggest that ACE-I and ARBs have the ability to improve glycemic control by improving insulin sensitivity. **Table 1** provides a brief description of the studies and their findings. This chapter explores the possibility of utilizing RAAS inhibitors as a means of diabetes prevention and/or improved glucose tolerance and the potential mechanisms by which this could be accomplished.

#### **2. RAAS and glucose homeostasis**

The renin-angiotensin-aldosterone system (RAAS) is responsible for regulating arterial blood pressure and blood volume [20, 21]. Renin, an enzyme produced by the juxtaglomerular cells in the kidney in response to low blood pressure or decreased sodium delivery to the kidneys, converts angiotensinogen to angiotensin I. Angiotensin converting enzyme (ACE), found in the lungs and kidneys, then converts angiotensin I to angiotensin II (AG II). Angiotensin II is the predominant hormone responsible for the hemodynamic effects of RAAS, namely: sodium retention at the proximal convoluted tubules of the kidneys, arterial vasoconstriction, and release of aldosterone from the adrenal glands [22]. Angiotensin II is also responsible for the non-hemodynamic effect of RAAS related to glucose hemostasis [21, 23]. Several studies have suggested the role of RAAS in the development of insulin resistance and subsequent development of type 2 diabetes mellitus (T2DM) in humans. The pathophysiology is complex, mostly involving the skeletal muscle, adipose tissue, and pancreas [21] (**Figure 1**).

1.**RAAS and the skeletal muscle:** AG II affects glucose metabolism in the skeletal muscle through the inhibition of insulin-mediated glucose uptake and insulin signaling pathway, and a decrease in the blood supply to the skeletal muscle [21].

*Inhibition of insulin-mediated glucose uptake and insulin signaling pathway.* The skeletal muscle accounts for up to 70% of insulin-mediated glucose uptake in the body, which occurs through a series of tightly regulated events in the insulin signaling pathway [23, 24]. First, insulin binds to the insulin receptor on the

*Renin Angiotensin Aldosterone System, Glucose Homeostasis, and Prevention of Type 2... DOI: http://dx.doi.org/10.5772/intechopen.97737*

surface of the skeletal muscle cell, and this activates a cascade of events that ultimately ends in translocation of the glucose transporters (GLUT-4) from intracellular vesicles to the cell membrane through which glucose is taken up by the cells [23, 24]. Therefore, inhibition at any stage in the signaling pathway will result in insulin resistance with subsequent type 2 diabetes development if left unresolved. By acting through the angiotensin II type 1 receptor (AT1R), AG II activates NADPH oxidase, which leads to the production of reactive oxygen species that in turn inhibits insulin-mediated translocation of GLUT-4 transporters, glucose uptake, and insulin signaling pathway in the skeletal muscle [23, 24].

*Decrease in the blood supply to the skeletal muscle*. Studies also show that AG II contributes to insulin resistance by decreasing microvascular blood supply to the skeletal muscle [21].


In summary, through its different effects on the skeletal muscle, adipose tissue, and pancreas, RAAS is thought to contribute to the development of insulin resistance and development of type 2 diabetes. Therapy with RAAS inhibitors has been

**Figure 1.**

*Potential mechanisms implicated in favorable glycemic effect associated with RAAS inhibition.*

indeed associated with favorable glycemic events. At a clinical level, several trials have examined the role of RAAS inhibition in preventing the development of type 2 diabetes in the population at risk.

#### **3. Diabetes prevention as a secondary outcome of RAAS inhibition trials**

There have been a number of trials conducted in which the primary aim was to study the effect of RAAS inhibitors on CVD and events. In addition to this primary outcome of interest, a number of these trials have found positive results with regards to their effect on diabetes prevention and improved glucose tolerance.

One of the first clinical trials to demonstrate a protective effect of RAAS inhibition on the incidence of diabetes was the Captopril Prevention Project (CAPPP) initiated in 1999. The primary aim of this trial was to compare the effect of ACE inhibition (using captopril) with conventional therapy (-blockers and/or diuretics) on risk of CVD morbidity and mortality in patients with hypertension [26]. While there was no difference in prevention of cardiovascular morbidity and mortality in those treated with captopril compared with conventional therapy, authors did find that the incidence of new onset diabetes was lower in participants treated with captopril [26]. This finding supports the theory that ACE inhibition may work to prevent the development of diabetes, which may be due to captopril's ability to improve insulin sensitivity [26]. Additionally, those patients with diabetes at baseline who were treated with captopril had a lower rate of cardiovascular events and mortality when compared to those with diabetes treated with conventional therapy [26].

Another study, the Heart Outcomes Prevention Evaluation (HOPE) study, sought to explore the role of the ACE inhibitor, ramipril, on the incidence of myocardial infarction (MI), stroke, or all-cause mortality in patients with a history of vascular disease (coronary artery disease, stroke, peripheral vascular disease) or diabetes, plus at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low high-density lipoprotein cholesterol levels, cigarette smoking, or microalbuminuria), but without heart failure or any degree of left ventricular dysfunction [27]. Subjects were randomized to receive ramipril or placebo, both with the addition of 400 IU of vitamin E daily [27]. Of the primary outcomes examined, patients treated with ramipril had a significantly decreased risk of myocardial infarction, stroke, or death from cardiovascular causes (RR 0.78, 95% CI 0.70–0.86). Of the participants without a diagnosis of diabetes at study onset, there was a 34% decreased incidence of new onset diabetes in those treated with ramipril compared with placebo (RR 0.66, 95% CI 0.34–0.76) [27]. Of note, these results are consistent with the study to Evaluate Carotid Ultrasound changes in patients treated with ramipril and vitamin E (SECURE), which reported decreased fasting glucose levels in patients treated with ramipril when compared with placebo [28].

Another trial, the Losartan Intervention For Endpoint reduction in hypertension study (LIFE), randomized participants aged 55–80 years with hypertension and electrocardiographic left ventricular hypertrophy (ECG LVH) to either losartan or atenolol [29]. The primary aim of this trial was to determine whether losartan improves LVH and thus reduces cardiovascular morbidity and mortality. Results revealed that those participants who received losartan had a decreased risk of cardiovascular events (MI and stroke), and 25% decreased risk of new onset DM when compared with atenolol (HR 0.75, 95% CI 0.63–0.88, p 0.001) [30]. It is possible that the protective effect of losartan on diabetes incidence seen in the LIFE trial could be due to the detrimental effects of atenolol, a -blocker, on insulin sensitivity [10].

#### *Renin Angiotensin Aldosterone System, Glucose Homeostasis, and Prevention of Type 2... DOI: http://dx.doi.org/10.5772/intechopen.97737*

The presence of diabetes has been found to be associated with increased left ventricular hypertrophy, both of which are risk factors for the cardiometabolic syndrome [29]. The initial analysis of the LIFE trial found that individuals treated with losartan had an increased regression of LVH when compared to those treated with atenolol. However, patients with diabetes and LVH had less regression than those without diabetes, possibly secondary to their predisposition [29]. A secondary analysis was conducted on the participants without diabetes at baseline, which sought to determine whether in-treatment resolution or continued absence of ECG LVH is associated with decreased risk of developing diabetes [29]. This analysis revealed a 38% decreased incidence of DM in those who had resolution or continued absence of LVH (HR 0.62, 95% CI 0.50–0.78, p < 0.001) independent of the previously identified effects of treatment with losartan versus atenolol. This finding suggests that while DM might lead to LVH, it is possible that LVH may in fact precede the development of diabetes [29]. While the causality of this relationship is uncertain, this study proposes the idea that regression of LVH by means of RAAS inhibition might decrease the risk for DM. However, it is also possible that this observed relationship between LVH regression and decreased incidence of DM can be explained by the established association between hypertension and insulin resistance. This idea aligns with the finding that participants of the LIFE trial who developed diabetes had higher baseline systolic and diastolic blood pressures than those who did not [29].

In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, the primary aim was to compare the effectiveness of treatment with diuretic, chlorthalidone against calcium channel blocker, amlodipine and ACE-I, lisinopril in preventing coronary heart disease (CHD) or other cardiovascular events in patients with hypertension and at least one CHD risk factor [31]. As far as primary outcome of interest, chlorthalidone was found to be superior to the others in preventing the primary outcome. However, study participants on lisinopril were found to have a lower incidence of diabetes at the follow up period of four years, when compared to those placed on other antihypertensives [31].

Similarly, the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial sought to determine whether treatment with another ACE-I, trandolapril in patients with stable CAD and left ventricular ejection fraction (LVEF) > 40% would reduce cardiovascular deaths, incidence of MI or need for percutaneous coronary intervention (PCI) when compared with treatment with placebo [32]. Although a secondary end point, results from this trial revealed that the incidence of new onset DM was significantly decreased in those treated with trandolapril when compared to those in the placebo group (HR 0.83, 95%CI 0.72–0.96, p=0.01) [32]. Results from the PEACE trial, similar to the HOPE trial are important because they cannot be attributed to the adverse effects of the comparison drug (placebo).

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial compared coronary heart disease outcomes in patients with hypertension treated with valsartan or amlodipine [33]. While there were no differences in primary composite outcome of cardiovascular morbidity and mortality in either group, secondary analysis revealed that new-onset DM occurred significantly less in patients treated with valsartan [33]. Despite the observed decreased incidence of diabetes with valsartan use, blood pressure reduction was less in this group, compared to those treated with amlodipine, which suggests that the effect of ARBs on diabetes prevention is independent of blood pressure reduction [34].

While each of the above trials found treatment with ACE-I and ARBs to be associated with decreased incidence of new onset diabetes, it must be noted that diabetes prevention was not a defined primary outcome in any of these studies.

Thus, their results must be interpreted with caution. A few other weaknesses should be taken into consideration on review. Some of these trials, including the HOPE and PEACE trials did not perform formal glucose testing to establish glycemic status, and relied on self-report alone [32, 35, 36]. Additionally, the HOPE, CAPP, and LIFE trials all utilized -blockers as comparator drugs, which allows for the possibility that the observed effect of therapy with ACE-I or ARB on diabetes prevention is due to the detrimental effects of B-blockers on development of diabetes rather than the benefits of RAAS inhibition. A large prospective cohort study (n=12,550) conducted in 2000 revealed that hypertensive patients taking -blockers had a 28% increased risk of diabetes when compared to those who were not on any antihypertensive therapy [37].

#### **4. DREAM and NAVIGATOR trials**

Studies including the aforementioned trials showed a beneficial effect of RAAS inhibition with ACE-I and ARBs on diabetes prevention among patients with hypertension and other cardiovascular diseases [30, 35, 38, 39]. These trials studied diabetes prevention as a secondary outcome or post hoc analysis, thus the results should be interpreted with caution. Conversely, the DREAM and NAVIGATOR trials, conducted in 2006 and 2008, respectively, are double blind, randomized clinical trials, which were designed to determine the effect of RAAS inhibition on the incidence of diabetes as a primary outcome [40, 41]. Furthermore, in these two trials, glycemic categories were meticulously determined, defined and recorded. In both studies, DM was defined using standard criteria, fasting blood glucose (FBG) 126 mg/dl or 200 mg/dl post oral glucose load and confirmed again at a later date. In the DREAM study, even in the event that diabetes was diagnosed by an outside physician, confirmation of the diagnosis using standard plasma glucose criteria was required in addition to the prescription of an antidiabetic agent by the diagnosing physician [40].

The DREAM trial was designed to investigate the effect of ramipril, an ACE-I and rosiglitazone, a thiazolidinedione, on diabetes prevention among patients with prediabetes (IGT and/or IFG) but without cardiovascular disease. The primary outcome of this study was newly diagnosed diabetes or death, with a secondary outcome of regression to normoglycemia defined as normal fasting and 2 hour post-load glucose levels [40]. Data analysis revealed no significant difference in the development of diabetes in the ramipril group when compared to the placebo group (HR 0.91, 95% CI 0.80–1.03) [40]. However, the likelihood of regression to normoglycemia was increased among subjects within the ramipril group when compared to the placebo group (HR 1.16, 95% CI 1.07–1.27). Moreover, while the fasting plasma glucose levels did not differ between the ramipril and the placebo group at the end of the trial, the 2 hour post glucose oral load values were significantly lower among those within the ramipril group [40].

There are a number of possible explanations for the lack of reduction in DM incidence with ramipril use in the DREAM trial which was different from the results found in previous trials with ACE-I/ARBs. First, as mentioned, diagnosis of diabetes at study onset was unambiguously established in participants of the DREAM trial with an oral glucose tolerance test (OGTT), thus patients with pre-existing DM were reliably excluded from the study [40]. This was not the case for some of the other studies mentioned previously [35, 42]. Second, the demographics of the DREAM study patients differed from those of trials which showed a reduced incidence of DM with RAAS inhibitors. Compared to the participants of the DREAM trial, subjects from the other trials were older, and had established CVD, and/or

#### *Renin Angiotensin Aldosterone System, Glucose Homeostasis, and Prevention of Type 2... DOI: http://dx.doi.org/10.5772/intechopen.97737*

heart failure [30, 35, 36, 43, 44]. It is possible that the RAAS system is activated to a greater extent and thus ACE inhibition may have greater benefits in these individuals [45]. Third, some of the trials that revealed reduced incidence of DM among those treated with ACE-I/ARBs had compared ACE-I with other anti-hypertensives associated with dysglycemia, such as -blockers, as mentioned previously. This may have led to a possible exaggeration of the effect of RAAS inhibition on diabetes prevention. Fourth, most of the previous trials that showed a beneficial effect of ACE-I And ARB on DM prevention followed the patients for longer period of time than the median 3 years that the participants of the DREAM trial were followed for [30, 32, 35, 39, 43]. Specifically, the participants of the HOPE trial were followed for 4.5 years, the PEACE trial for 4.8 years, ALLHAT study for 4.9 years, and the LIFE study for 4.8 years [30, 32, 35, 39]. In the DREAM trial, there was a late diversion of the Kaplan–Meier curves that suggested a benefit of ramipril in DM prevention after 3–5 years. Thus, it is possible that a longer and larger study may be needed to observe the effect of ramipril on DM prevention [45].

Four years after the publication of the results of the DREAM trial, the results of another trial, the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, were released [41]. This study also sought to investigate the effect of RAAS inhibition with the ARB, valsartan in addition to lifestyle modification on diabetes prevention in patients with impaired glucose tolerance and established CVD or CVD risk factors.

The NAVIGATOR trial was an improvement over the DREAM trial in several ways. First, a study-specific lifestyle-intervention program, which has previously been found to reduce risk of diabetes by up to 50%, was implemented for all patients in addition to pharmacotherapy [46, 47]. Second, there was a longer median follow up of 5 years in the NAVIGATOR trial compared with the 3 years follow up in the DREAM trial [40, 41]. Third, the NAVIGATOR trial enrolled a larger number of participants, 9306, versus 5269 participants in the DREAM trial. Another difference between these studies is that, unlike the DREAM trial, the NAVIGATOR trial enrolled patients with established CVD or CVD risk factors, who may have a greater degree of RAAS activation at baseline.

With these differences in mind, it is not surprising that while the DREAM trial found no difference between the ramipril and placebo groups with regards to diabetes prevention, the NAVIGATOR trial found that those treated with valsartan had a significantly reduced incidence of DM by 14% (HR 0.86, 95% CI 0.80–0.92, p< 0.001). Furthermore, patients in the valsartan arm of the study had lower mean fasting plasma glucose and 2 hours post glucose load levels. Additionally, the proportion of patients taking glucose lowering agents at the end of the study was lower in the valsartan group than in those in the placebo group.

Although significant, the 14% reduction in diabetes risk with valsartan appears smaller than the risk reduction seen in previously conducted trials involving ACE-I and ARBs [32, 35, 36, 44, 48]. One possible reason is that by the last study visit, a significantly higher proportion of subjects in the placebo arm were taking other ARBs or ACE-I (24.4% vs. 21.8%), which could have diluted the effect seen with valsartan. Another reason for this observed discrepancy could be due to a difference in the way in which glycemic status was determined at study onset and completion. Unlike the NAVIGATOR trial, a few other trials diagnosed DM by self-report rather than formal glucose testing which allows for misclassification error and possible false exaggeration of results [35].

In addition, the effect of valsartan with lifestyle modification was much smaller compared to landmark studies on diabetes prevention with lifestyle alone in which the incidence of DM was reduced by as much as 58% [46, 47, 49]. Similarly, the effect of valsartan on diabetes prevention in the NAVIGATOR trial is smaller when

compared to glucose lowering agents such as metformin, 26–31% [46, 50], acarbose 25% [51] and rosiglitazone 60% in the DREAM study [52]. It is worthy of note that the NAVIGATOR trial followed the subjects for a longer duration (5 years) compared to the trials involving these glucose lowering agents in which subjects were followed for 2.5–3.3 years.

In conclusion, the DREAM and NAVIGATOR trials showed benefit in glycemic indices but only the NAVIGATOR trial showed a reduced diabetes incidence as a primary outcome of RAAS inhibition with ACE-I and ARBs. These findings may have utility in the clinical setting, in terms of choice of antihypertensive agents to those at higher risk of DM development, in the presence or absence of CVD and its risk factors.

#### **5. Conclusion and clinical implications**

ACE-I and ARBs are currently widely used for the treatment of patients with hypertension, heart failure or asymptomatic left ventricular dysfunction, coronary artery disease, and diabetic nephropathy, with the clinical benefits of ACE-I more closely studied [53]. Based on the results from the aforementioned trials, the use of these agents may also be indicated for the prevention of diabetes and/or regression from impaired to normoglycemia. This is extremely significant in light of the emerging diabetes epidemic.

While it is not entirely clear, results from the trials explored throughout this chapter suggest that those with cardiometabolic syndrome and its risk factors including (but not limited to) hypertension, obesity, insulin resistance, and left ventricular hypertrophy may experience the greatest benefits with regards to diabetes prevention and improved glycemic control. This could be due to the fact that the RAAS system is overactive in a number of these conditions. As discussed, activation of the RAAS system and increased production of angiotensin II is thought to play a role in the development of insulin resistance and subsequent development of T2DM [21]. It is also possible that the ability of ACE-I and ARBs to prevent diabetes is in part due to their effect on blood pressure reduction and LVH regression, both of which have been shown to improve insulin sensitivity [29].

However, while results from the CAPPP trial found a decreased incidence of new onset DM in patients treated with captopril, the blood pressure of patients in this group was significantly higher throughout the study than those treated with conventional therapy with -blocker and/or diuretics. This supports the hypothesis that captopril's effect on diabetes prevention might be independent of blood pressure reduction. Results from the sub-analysis of the LIFE trial suggests that the effect of RAAS inhibition with losartan on LVH regression may be partly responsible for the decreased incidence of DM. It is possible that this association is also explained in part by the relationship between blood pressure and insulin resistance [29]. In conclusion, the apparent decreased incidence of new onset diabetes seen in patients treated with ACE-I and ARBs are likely attributable to both direct and indirect effects of these agents.

Given the variety of indications for which RAAS inhibitors have been established, the additional benefit of diabetes prevention could help to alleviate polypharmacy in individuals who suffer from several of these conditions simultaneously. However, more research is needed to categorically place ACE-I and ARBs among the armamentarium of agents favoring DM prevention. Head to head studies comparing the effects of different ACE-I and ARBs would also be useful.

*Renin Angiotensin Aldosterone System, Glucose Homeostasis, and Prevention of Type 2... DOI: http://dx.doi.org/10.5772/intechopen.97737*

#### **Author details**

Samara Skwiersky1 , Sandra Iwuala1 , Seeta Chillumuntala1 , Deborah Osafehinti<sup>2</sup> and Jocelyne Karam1,2\*

1 SUNY-Downstate, Health Science University, Brooklyn, NY, USA

2 Maimonides Medical Center, Brooklyn, NY, USA

\*Address all correspondence to: jkaram@maimonidesmed.org

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### Section 3
