The Renin-Angiotensin Aldosterone System: Pathophysiologic Insights

#### **Chapter 1**

## The Role of the Renin-Angiotensin-Aldosterone System in Cardiovascular Disease: Pathogenetic Insights and Clinical Implications

*Violeta Capric, Harshith Priyan Chandrakumar, Jessica Celenza-Salvatore and Amgad N. Makaryus*

#### **Abstract**

Increased attention has been placed on the activation of the reninangiotensin-aldosterone system (RAAS) and pathogenetic mechanisms in cardiovascular disease. Multiple studies have presented data to suggest that cardiac and arterial stiffness leading to adverse remodeling of both the heart and vasculature leads to the various pathological changes seen in coronary artery disease, heart failure (with preserved and reduced ejection fractions), hypertension and renal disease. Over-activation of the RAAS is felt to contribute to these structural and endocrinological changes through its control of the Na+/K+ balance, fluid volume, and hemodynamic stability. Subsequently, along these lines, multiple large investigations have shown that RAAS blockade contributes to prevention of both cardiovascular and renal disease. We aim to highlight the known role of the activated RAAS and provide an updated description of the mechanisms by which activation of RAAS promotes and leads to the pathogenesis of cardiovascular disease.

**Keywords:** cardiovascular disease, coronary artery disease, heart failure, hypertension

#### **1. Introduction**

Cardiovascular disease is the leading cause of death in men and women in the United States and throughout the world [1]. Current efforts are focused on decreasing the burden of death due to atherosclerosis and cardiac disease overall. Increased attention has been placed on the activation of the renin-angiotensin-aldosterone system (RAAS) and pathogenetic mechanisms in cardiovascular disease. The RAAS system effects blood pressure control and electrolyte and fluid balance and therefore plays a significant role in cardiovascular hemodynamics [2–4].

Classically, it is known that angiotensinogen is cleaved by renin to form angiotensin-I (Ang I), which is then converted to angiotensin-II (Ang II) by angiotensin converting enzyme (ACE), however other peptides and products of this axis have

been shown to play a role in the development of cardiovascular disease [3, 4]. It is thought that two of these products (angiotensin 1-7 and angiotensin 1-9) may have counterregulatory effects on the development of atherosclerosis and cardiovascular disease [4]. Although the role of angiotensin II is understood more clearly, these peptides provide other targets by which the RAAS system can be utilized to prevent atherosclerosis.

Overactivation or pathologic activation of the RAAS system, specifically angiotensin II, has been shown to play a specific role in endothelial dysfunction, inflammation, intense vasoconstriction, increased vascular and cardiac hypertrophy, fibrosis and the development of atherosclerosis [2–5]. Multiple large investigations have shown that direct inhibition of the effects of angiotensin II via angiotensin converting enzyme inhibitors (ACE-I) and angiotensin-receptor blockers (ARB) improve mortality, prevent renal disease and decrease cardiovascular events in this subset of patients. Additionally, some studies have shown that utilization of both ARB and ACE-I may have cumulative effects on inhibiting the adverse effects of an overactivated RAAS system [6, 7].

We aim to highlight the known role of the activated RAAS and provide an updated description of the mechanisms by which overactivation of RAAS promotes disease and provide a summary of the clinical implications of RAAS inhibition in cardiovascular disease.

#### **2. Overview of the RAAS system**

The RAAS system has several moving parts, with different organ systems stimulating its activation and suppression. Renin, the active form of prorenin, is secreted by the granular cells of the kidney. Although renin's role is that of an enzyme, its means of expression are more hormonal. Renin's production is stimulated by hypotension, hyponatremia, and decreased sympathetic activity. Renin is responsible for cleaving angiotensinogen, a protein produced in the liver. Angiotensinogen is regulated via thyroid hormone, steroids, and levels of circulating angiotensin II. Angiotensinogen is cleaved into angiotensin I, which is further converted into angiotensin II by angiotensin converting enzyme [3, 4].

RAAS key players are composed of renin, angiotensin I & II, and angiotensin converting enzyme located in the heart atria, conduction system, valves, ventricles, coronary vessels, fibroblasts and myocytes [8, 9]. Ang II is the effector hormone playing a pivotal role in the cardiac RAAS and has a widespread effect throughout the body, targeting different mechanisms of action.

Ang II acts via the angiotensin receptors mediating the following actions [9, 10]:


Angiotensin converting enzyme 2 (ACE 2) is involved in the degradation of Ang II to Ang (1-7) and Ang (1-9), which provide a relative vasodilatory effect

*The Role of the Renin-Angiotensin-Aldosterone System in Cardiovascular Disease… DOI: http://dx.doi.org/10.5772/intechopen.96415*

**Figure 1.**

*Schematic of the RAAS as it pertains to angiotensin II and angiotensin (1-7) (Ang-(1-7)) and their counterregulatory effects via angiotensin receptors 1 and 2 (AT1-R and AT2-R respectively) and MAS receptor (MAS) [5, 6, 11]. Abbreviations: ACE-I (angiotensin converting enzyme inhibitor), ARB (Angiotensin-II receptor blocker), Ang (1-9) (angiotensin 1-9), ACE (angiotensin converting enzyme).*

as outlined in **Figure 1**. ACE 2 is restricted to vascular endothelial cells, arterial smooth muscle cells, myofibroblasts, carotid arteries and renal tubular epithelium [8–10]. The effects of Ang II, Ang (1-7) and Ang (1-9) have been uncovered in the past several years, specifically their role in hypertension, endothelial damage, and cardiovascular disease [5, 6, 9, 12]. The role of Ang (1-7) and Ang (1-9) is further outlined in **Figure 1** as they pertain to the pathophysiologic changes in the cardiovascular system.

#### **3. Pathogenic insights**

#### **3.1 Atherosclerosis and endothelial dysfunction**

Endothelial dysfunction is thought to be a precursor to atherosclerosis, or the thickening and stiffness of vessels. This damage often cultivates in an atherosclerotic plaque, which is a fibrin and cholesterol contained structure that deposits on the inner lumen of blood vessels and can impede oxygen delivery to tissues and organs. Endothelial damage and inflammation allow for the migration of monocytes and macrophages to the site of injury and the formation of foam cells [13–15]. Additionally, stimulation of inflammatory mediators also promotes smooth muscle cell (SMC) thickening, stiffness of vessels and forms a fibrous cap on the atherosclerotic plaque (**Figure 2**) [16]. The pathophysiology of plaque development is very closely tied to RAAS as Ang II plays a key role in these pathophysiologic changes.

Ang II acts on the AT1 and AT2 receptors (AT1-R and AT2-R) causing arteriolar vasoconstriction, and inflammation through generation of reactive oxygen species

#### **Figure 2.**

*A schematic depicting the dynamic changes involved in the formation of an atherosclerotic plaque [16]. Abbreviations: ROS, reactive oxygen species; ICAM-1, intracellular adhesion molecule 1; IFN-c, interferongamma; IL, interleukin; LDL, low-density lipoprotein; M-CSF, macrophage colony-stimulating factor; MCP-1, monocyte chemoattractant protein 1; MMP, matrix metalloproteinase; oxLDL, oxidized LDL; SR-A, scavenger receptor A; TGF-b, transforming growth factor beta; VCAM-1, vascular adhesion molecule 1; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cells. Reproduced with permission from Mary Ann Liebert, Inc.*

(ROS), proinflammatory transcription factors such as nuclear factor kB (nf-kB), and the proliferation of smooth muscle cells contributing to atherogenesis [17, 18]. Activated nf-kB increases inflammatory mediators including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and platelet derived growth factor (PDGF), all of which mediate inflammation, endothelial damage and monocyte migration and adhesion leading to fibrosis [6, 18].

Ang II induces NF-kappaB (NF-kB) and inflammation through its binding to AT1-R. This has been demonstrated extensively as AT1-R blockers have shown to significantly decrease inflammation. Induction of NF-kB leads to the expression of pro-inflammatory cytokines such as IL-6 and TNF-alpha [19, 20]. Additionally, IL-6 itself can activate AT1-R resulting in overexpression and production of reactive oxidative species (ROS) when RAAS is overstimulated [19]. The RAAS is also a potent oxidant stimulator, as it activates the NADH/NADPH oxidase signaling pathway, and thereby produces superoxide anions and other ROS. TNF-alpha impairs endothelial nitric oxide (NO) production in coronary arteries thereby causing vasoconstriction. Additionally, ACE plays a role in the degradation of bradykinin, which depletes NO formation as well [6, 18–20]. Overall, we have a RAAS mediated expression of ROS, inflammatory mediators, and depletion of vasodilatory NO.

This inflammation mediated cellular injury and production of ROS, activates the endothelium and increases expression of intercellular adhesion molecules (ICAM-1) and vascular cell adhesion molecules (VCAM-1), which promote endothelial damage and make cells leaky [9, 21, 22]. The endothelial damage promotes further migration of leukocytes, production of inflammatory cytokines and chemokines.

Finally, RAAS promotes thrombosis through Ang II receptors located on human platelets. Through these receptors Ang II promotes the release of thromboxane A2

*The Role of the Renin-Angiotensin-Aldosterone System in Cardiovascular Disease… DOI: http://dx.doi.org/10.5772/intechopen.96415*

#### **Figure 3.**

*Summarized effects of Ang II as it is known to cause endothelial damage, inflammation, migration and adhesion of monocytes, proliferation of vasculature and platelets and formation of atherosclerotic plaque and thrombus [6, 18–23].*

and platelet derived growth factor, which promote atherosclerotic plaque formation and thrombus formation [22, 23]. Ang II involvement in endothelial dysfunction and atherosclerotic plaque formation is summarized in **Figure 3**.

#### **4. Hypertension**

Hypertension, defined as a systolic blood pressure greater than 120 and diastolic pressure greater than 80, affects a quarter of the world's population. When the etiology of hypertension is unknown, it is termed essential hypertension. When the cause of hypertension is known, by way of underlying metabolic, hormonal, neurogenic, or cardiovascular dysfunction, it is deemed as secondary hypertension [24]. As we have reviewed thus far, RAAS is responsible for maintaining sodium concentration in the blood, fluid status, and hemodynamic stability and therefore has a significant effect on blood pressure. Overactivation of RAAS can perpetuate unwanted elevations in blood pressure.

Increased levels of Ang II and subsequently aldosterone cause increases in vascular tone and hypertension. Aldosterone, a mineralocorticoid, takes its effect by binding to mineralocorticoid receptors (MR) and translocating into nucleus. Here, it integrates with cellular DNA and induces transcription of genes that regulate electrolytes and fluid balance. An over expression of aldosterone causes an elevated aldosterone-renin ratio which leads to systemic complications [4].

Patient's with primary aldosteronism (PA) and increased aldosterone levels are at higher risk for cerebrovascular complications. Although PA is not a common diagnosis, fifteen percent of patients with essential hypertension have higher than normal levels of circulating aldosterone. We can conclude that this sub-set of essential hypertension patients will have similar end-organ effects of elevated aldosterone as do patients with PA [4].

Hypertension itself can cause endovascular injury, which leads to increased production of ROS and inflammatory mediators ultimately contributing to atherosclerosis [25, 26]. The result of such endothelial injury is worsening cardiovascular disease, hypertension, and renal dysfunction. We see this manifest in the kidney with proteinuria and collagen deposition. Eventually, healthy kidney parenchyma is replaced with fibrotic tissue, leading to even more dysregulation with blood

pressure homeostasis. In the cardiovascular system, inflammatory damage from overactivation of RAAS and hypertension causes calcifications and fibrosis. As such, inhibition of the RAAS system with ACE-I and ARB has become a cornerstone in therapy for hypertensive patients, particularly those with evidence of diabetes, microalbuminuria and in CAD patients overall [15, 25–28]. The details of some of the landmark clinical trials contributing to the guidelines in treatment with ACE-I and ARB are further discussed in this chapter.

#### **5. Ischemic heart disease**

Coronary artery disease (CAD) or Ischemic heart disease (IHD), develops when there is a limitation of blood flow within the coronaries. It occurs due to the gradual buildup of atherosclerotic plaque within the wall of arteries leading to reduced oxygen delivery to cardiac myocytes. It comprises a clinical spectrum based on the degree of luminal narrowing and the activation of the atherosclerotic plaque [13, 14]. The RAAS plays a vital role in the pathogenesis of CAD. Evidence supports that RAAS controls atherosclerosis through intracellular signaling pathways by mediating endothelial function, inflammation, fibrinolytic balance, growth, lipid-glucose metabolism, and its vasoconstrictor function.

Ang II has growth promoting effects by regulating growth of vascular smooth muscle cells and activating the growth associated kinase pathways. In states of ischemia, there is increased vascular endothelial growth factor (VEGF) expression. In vascular smooth muscle cells, transforming growth factor B1, platelet derived growth factor causes fibrosis and cellular hypertrophy. These angiogenic factors lead to the formation of new cells, fibrin, and collagen deposition leading to growth of the plaque and thickening of vessels [20, 21].

RAAS plays a role in altering the fibrinolytic balance as well by inhibiting fibrinolysis and enhancing thrombosis. Within the vessels, Ang II stimulates the release of plasminogen activator inhibitor - I (PAI-I) thereby reducing the fibrinolytic activity. It activates tissue factor which acts as a cofactor for factor VII, potentiating the coagulation cascade [22, 23]. The above mechanism increases the thrombogenic activity.

Ang II overexpression causes endothelial inflammation and activation of cytokine cascade thereby causing progression of atherosclerotic plaque. The silent plaque ruptures when the inflammation overwhelms the stable fibrous cap causing thrombosis and acute ischemia [13, 14].

#### **6. Heart failure**

Heart failure is a clinical syndrome categorized based on clinical signs and symptoms and further subclassified by echocardiography findings. As per the American College of Cardiology, left ventricular ejection fraction (LVEF) of ≥50% is defined as heart failure with preserved ejection fraction (HFpEF), LVEF 41-49% as heart failure with mid-range ejection fraction (HFmrEF), LVEF≤40% as heart failure with reduced ejection fraction (HFrEF). HFrEF particularly occurs after an inciting event like myocardial injury, arrhythmias, cardiomyopathies, substance abuse, infections or genetic diseases which put the heart in a state of stress leading to contractile dysfunction and cellular remodeling [29]. The circulatory changes arising from heart failure are sensed by the peripheral baroreceptors and chemoreceptors, thereby activating a sequalae of compensatory neurohormonal mechanisms. The compensatory mechanisms include activation of sympathetic nervous

*The Role of the Renin-Angiotensin-Aldosterone System in Cardiovascular Disease… DOI: http://dx.doi.org/10.5772/intechopen.96415*

system (SNS) and RAAS. RAAS plays an integral role in cardiac contractility, homeostatic control of blood pressure and electrolyte-fluid balance [30, 31].

In an adult with normal circulation, the baroreceptors located in the carotid sinus and aortic arch balance the sympathetic and parasympathetic outflow from the central nervous system. Alterations in the cardiac output change the effective arterial blood volume resulting in inhibition of parasympathetic response and a reflux increase in the sympathetic vascular tone. The increased sympathetic activity leads to vasoconstriction of the renal afferent arteriole and decreases blood flow to the kidney [29, 32]. This activates renin secretion and thereby RAAS.

Renin is secreted in response to 4 main stimuli [10, 33]:


The pathophysiology of heart failure allows for decreased renal perfusion and increased sympathetic response, both of which cause an overactivation of the RAAS [34]. The overstimulation of RAAS in heart failure is further depicted in **Figure 4**.

In pathological states like pressure or volume overload, cardiac tissues exhibit elevated levels of renin and Ang II levels leading to cardiac hypertrophy, myocardial fibrosis, hypertensive heart disease and chronic heart failure through mechanics explained earlier. Additionally, post-infarction levels of ACE-2 have been shown to be elevated, which may explain a counter-regulatory mechanism to protect against the Ang-II mediated myocardial damage. When this natural counter-regulatory mechanism is lost in ACE-2 knockout animal models the levels of dilated cardiomyopathy were much more pronounced. Several trials have also looked at specific levels of plasma renin and HFrEF and have found that those with elevated levels had an associated worse outcome than their counterparts. In patients with advanced heart failure, baseline levels of plasma renin and plasma aldosterone are persistently high, which further exemplifies the role of RAAS in cardiac remodeling and heart failure [35–37].

#### **Figure 4.**

*The regulatory effects of RAAS as it pertains to heart failure mechanics [34]. Reproduced with permission from McGraw Hill LLC.*

Innovative studies have discovered that a particular breakdown product of Ang 1-7, also known as Alamandine, has shown to prevent ventricular and vascular remodeling in animal models [11]. Studies of by-products offer areas of potential research as we grow to understand the intricacies of the molecular pathways that play a role in the development of heart failure.

#### **7. Clinical implications**

The overactivation of RAAS and its effects on the pathophysiology of hypertension, vascular stiffness, ischemia, thrombosis, and left ventricular (LV) remodeling has been well documented. As such, several medications that impede the harmful effects of the overactivation of RAAS have been shown to prevent the negative clinical outcomes. Here we review some of the landmark clinical trials that have contributed to the current guidelines and recommendations for the treatment of hypertension, ischemic heart disease and heart failure (**Table 1**).

In the treatment of hypertension, the patient's specific co-morbidities must be considered prior to initiating therapy including, race, diabetes, kidney function and other high-risk pre-existing conditions that may predispose to CV outcomes. One landmark trial, the AASK trial (2002), studied African Americans with hypertension and kidney disease and compared intensive blood pressure control versus conservative blood pressure control with ACE-I, metoprolol, and amlodipine. The two groups had no difference in the progression to CKD, however patients on ACE-I had less chronic kidney disease events and death, which solidified the use of ACE-I in patients with CKD [38].

The mainstay of treatment in patients with heart failure and CAD is blockade of the RAAS. Multiple trials highlighted in **Table 1** have been performed showing improvement in cardiovascular (CV) outcomes and reduced CV mortality.

The first trial to demonstrate improved CV outcomes with HFrEF is the CONSENSUS (1987) trial conducted among New York Heart Association (NYHA) Class IV HF and cardiomegaly patients which compared enalapril and placebo. Six-month mortality with enalapril was 26% as opposed to 44% with placebo [39]. The SOLVD (1991) treatment trial chose patients with HF and LVEF ≤35%, NYHA II-IV, with similar randomization, showing mortality reduction by 16% due to reduction of death in patients on enalapril versus placebo. This study also showed a decrease in CV related hospitalizations [40]. Further research with the V-HeFT II (1991) trial showed that ACE-I was superior in improving survival to vasodilators such as isosorbide dinitrate and hydralazine [41]. Additionally, use of ACE-I as a disease modifying drug was established post-MI in the SAVE trial (1992), which is further discussed in **Table 1** [42].

Additional studies looked to compare the effects of ACE-I versus ARB. These trials were the VALIANT (2003) trial and the OPTIMAAL (2002) trial. The VALIANT trial showed that valsartan was as effective as captopril in improving survival among patients with HF and/or LV disfunction in the post-MI period [43]. The OPTIMAAL trial compared losartan and captopril in high-risk patients after acute myocardial infarction with LV-dysfunction and heart failure and found no difference in mortality outcomes [44]. Similar studies in patients with HFpEF were conducted, including the CHARM-Preserved trial (2003) and the I-PRESERVE trial (2008). CHARM- Preserved showed that candesartan modestly reduced HF-related hospitalizations however had no effect on mortality [45]. I-PRESERVE used Irbesartan in HFpEF patients and similarly found no reduction in mortality [46].

The thought that the addition of an ARB to an ACE inhibitor could inhibit RAAS more significantly was established. This was compared in two large significant


*The Role of the Renin-Angiotensin-Aldosterone System in Cardiovascular Disease… DOI: http://dx.doi.org/10.5772/intechopen.96415*



*The Role of the Renin-Angiotensin-Aldosterone System in Cardiovascular Disease… DOI: http://dx.doi.org/10.5772/intechopen.96415*

 *Trials documenting improvement in cardiovascular outcomes and reduced cardiovascular mortality with renin-angiotensin-aldosterone system inhibition.* trials. The CHARM-added trial compared symptomatic HF patients with LVEF ≤40% who were already on an ACE inhibitor with either addition of candesartan or placebo. This trial showed a reduction in CV mortality and HF hospitalizations; however, it was accompanied by a significant increase in hyperkalemic events [47]. The Val-HeFT (2001) compared patients with symptomatic HF, LVEF <40% with LV dilatation and on ACE inhibitors by adding either valsartan or placebo. There was no effect on mortality however, there was a 23% reduction in HF hospitalization in the treatment group [48]. Finally, the ONTARGET trial (2008) compared ramipril to telmisartan to a combination of both in patients with CV disease or diabetes with complications and found that the combination of telmisartan plus ramipril had no increase in benefit and was associated with more adverse events [49].

Several trials looking at the effects of aldosterone antagonists and heart failure patients were conducted with overall favorable results. Patients benefit from reduced sympathetic stimulation and alleviate fluid overload from sodium and water retention through aldosterone blockade. The RALES trial (1999) studied the role of spironolactone in patients with LVEF≤35% and NYHA class III-IV, which showed that Spironolactone, along with ACE-I (as most patients were already on ACE-I) showed a 11% reduction in CV mortality compared to placebo [50]. The TOPCAT trial (2014) done in patients with HFpEF and controlled blood pressures to receive spironolactone or placebo. This study conversely showed that spironolactone did not reduce CV mortality however did result in a small reduction in HF hospitalizations [51]. Another trial, the EMPHASIS-HF trial (2011), looked at Eplerenone versus placebo in HF patients, NYHA class II, showed that Eplerenone reduced the risk of death and hospitalizations in patients with HF [52].

A newer group of RAAS inhibition medications combining an ARB and neprilysin inhibitor (ARNI) was studied in 2014 in the PARADIGM-HF trial. Neprilysins are key enzymes in the degradation of natriuretic peptides. They increase endogenous natriuretic peptide levels including bradykinin, thereby promoting vasodilation and natriuresis. Neprilysins were initially attempted with an ACE inhibitor combination however this led to incidences of angioedema given increased levels of bradykinin. PARADIGM - HF trial was conducted in patients with symptomatic HF and LVEF ≤40% assigned to enalapril alone or valsartan-sacubitril combination. This showed significant reduction in CV mortality, all-cause mortality, and HF hospitalizations with no increase in angioedema events [53]. The PARAGON-HF trial (2019) studied ARNI versus valsartan alone in HFpEF patients with EF > 45% and NYHA II to IV and showed that ARNI did not lower hospitalizations or death from CV causes, however there was a modest improvement in NYHA class and a slower decline in renal function than what was seen in valsartan alone [54]. The PIONEER-HF trial (2019) showed that initiated of ARNI versus enalapril in acute diastolic heart failure patients allowed for significant reductions in HF biomarker, NT-proBNP, without significant change in adverse effects [55].

Direct renin inhibitors have been attempted with the goal of reducing renin and thereby the entire RAAS cascade. The ALTITUDE trial (2012) added aliskiren to patients with diabetes type 2 in order to prevent kidney disease and CV outcomes. These patients were on ACE-I however the addition of aliskiren led to an increase in CV mortality, hypotension, and adverse hyperkalemic events. The trial was stopped early due to higher mortality findings [56].

#### **8. Summary and conclusions**

RAAS is a complex and evolving pathway that has been implicated in the pathogenesis of endothelial damage, atherosclerosis, and cardiac remodeling. Inhibition

*The Role of the Renin-Angiotensin-Aldosterone System in Cardiovascular Disease… DOI: http://dx.doi.org/10.5772/intechopen.96415*

of the negative effects of overactivated RAAS has shown to cause morbidity and mortality benefits in cardiovascular disease outcomes. Significant research has yet to be performed on the possibility of stimulating the counter-regulatory effects of RAAS through AT2-R and MAS-R. Such mechanisms are still being studied in animal models; however, the effects of AT2-R and MAS-R offer potential areas of continued research and potential targets for future therapy.

#### **Conflict of interest**

No conflicts of interest exist for this work by any of the authors.

#### **Author details**

Violeta Capric1 , Harshith Priyan Chandrakumar1 , Jessica Celenza-Salvatore1 and Amgad N. Makaryus2,3\*

1 Department of Medicine, State University of New York-Downstate, Downstate-Health Science University, Brooklyn, NY, United States

2 Department of Cardiology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, United States

3 Department of Cardiology, Nassau University Medical Center, East Meadow, NY, United States

\*Address all correspondence to: amakaryu@numc.edu

© 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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[30] Dostal DE, Baker KM. The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? *Circ Res.* 1999 Oct 1;85(7):643-50. doi: 10.1161/01.res.85.7.643. PMID: 10506489

[31] Ruzicka M, Leenen FH. Relevance of blockade of cardiac and circulatory angiotensin-converting enzyme for the prevention of volume overload-induced cardiac hypertrophy. *Circulation*. 1995 Jan 1;91(1):16-9. doi: 10.1161/01. cir.91.1.16. PMID: 7805197.

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[34] Mann DL, Chakinala M. Heart Failure: Pathophysiology and Diagnosis. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. *Harrison's Principles of Internal Medicine, 20e*. McGraw-Hill; Accessed December 22, 2020.

[35] Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, Kubo SH, Rudin-Toretsky E, Yusuf S. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). *Circulation. 1990 Nov;82(5):1724-9. doi: 10.1161/01.cir.82.5.1724. PMID: 2146040.*

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[37] Mentz RJ, Stevens SR, DeVore AD, Lala A, Vader JM, AbouEzzeddine OF, Khazanie P, Redfield MM, Stevenson LW, O'Connor CM, Goldsmith SR, Bart BA, Anstrom KJ, Hernandez AF, Braunwald E, Felker GM. Decongestion strategies and renin-angiotensinaldosterone system activation in acute heart failure. *JACC Heart Fail.* 2015 Feb;3(2):97-107. doi: 10.1016/j. jchf.2014.09.003. Epub 2014 Oct 31. PMID: 25543972; PMCID: PMC4324057.

[38] Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG; African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. *JAMA*. 2002 Nov 20;288(19):2421- 31. Erratum in: *JAMA*. 2006 Jun 21;295(23):2726.

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[41] Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. *N Engl J Med. (*1991) 325(5):303-10.

[42] Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992 Sep 3;327(10):669-77. doi: 10.1056/NEJM199209033271001. PMID: 1386652.

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[45] Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. *Lancet*. (2003) 362(9386):777-81.

[46] Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A; I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. *N Engl J Med*. (2008) 359(23):2456-67.

[47] McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-convertingenzyme inhibitors: the CHARM-Added trial. Lancet. (2003) 362(9386):767-71.

[48] Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. *N Engl J Med*. (2001) 345(23):1667-75.

[49] ONTARGET Investigators: Yusuf S, Teo KK, et al.: Telmisartan, ramipril, or both in patients at high risk for vascular events. *N Engl J Med* (2008) 358:1547-1559.

[50] Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. *N Engl J Med.* (1999) 341(10):709-17.

[51] Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E,

Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. *N Engl J Med*. (2014) 370(15):1383-92.

[52] Zannad, F., McMurray, J. J. V., Krum, H., van Veldhuisen, D. J., Swedberg, K., Shi, H., … Pitt, B. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. *New England Journal of Medicine* (2011) 364(1), 11-21

[53] McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. *N Engl J Med*. (2014) 371(11):993-1004.

[54] Solomon, Scott D., et al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction: NEJM. *N Engl J Med* (2019) 381:1609-1620

[55] Velazquez, Eric J., et al. Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure: NEJM. *N Engl J Med* (2019) 380:539-548

[56] Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 Dec 6;367(23):2204-13.

#### **Chapter 2**

## Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics

### *A.H.M. Nurun Nabi and Akio Ebihara*

#### **Abstract**

Diabetes mellitus (DM) is a metabolic disorder and characterized by hyperglycemia. Being a concern of both the developed and developing world, diabetes is a global health burden and is a major cause of mortality world-wide. The most common is the type 2 diabetes mellitus (T2DM), which is mainly caused by resistance to insulin. Long-term complications of diabetes cause microvascular related problems (eg. nephropathy, neuropathy and retinopathy) along with macrovascular complications (eg. cardiovascular diseases, ischemic heart disease, peripheral vascular disease). Renin-angiotensinaldosterone system (RAAS) regulates homeostasis of body fluid that in turn, maintains blood pressure. Thus, RAAS plays pivotal role in the pathogenesis of long-term DM complications like cardiovascular diseases and chronic kidney diseases. T2DM is a polygenic disease, and the roles of RAAS components in insulin signaling pathway and insulin resistance have been well documented. Hyperglycemia has been found to be associated with the increased plasma renin activity, arterial pressure and renal vascular resistance. Several studies have reported involvement of single variants within particular genes in initiation and development of T2D using different approaches. This chapter aims to investigate and discuss potential genetic polymorphisms underlying T2D identified through candidate gene studies, genetic linkage studies, genome wide association studies.

**Keywords:** diabetes, type 2 diabetes, renin-angiotensin-aldosterone system, hypertension, gene polymorphism, genome wide association study, genetics, COVID-19

#### **1. Introduction**

Diabetes is a global health burden and one of the leading causes of morbidity world-wide [1]. Diabetes mellitus (DM) is a metabolic disorder characterized by polydipsia, polyphagia, polyurea and weight loss due to hyperglycemia, which means persistent elevated levels of plasma glucose. The prolonged hyperglycemia results in long-term impediments of diabetes that cause macrovascular complications including cardiovascular diseases (CVDs) and other vascular complications including nephropathy (end-stage renal disease) or retinopathy (leading to blindness) [2]. On the other hand, renin-angiotensin-aldosterone system (RAAS) plays an important role in maintaining blood pressure and body fluid [3]. Inappropriate activation of RAAS contributes to the hemodynamic abnormalities that lead to endothelial dysfunction, hypertension, and CVD [3, 4].

Diabetes, hypertension and CVDs, are important risk factors for severity and mortality in people infected with coronavirus infectious disease 2019 (COVID-19) [5, 6]. Both Type 2 diabetes (T2D), the commonest form of diabetes and hypertension are multifactorial and polygenic diseases caused by the association of both genetic and environmental factors. Understanding the underlying genetic causes of susceptibility to these diseases is important for people's health and health-related quality of life worldwide. In this chapter, we describe the pathophysiology of T2D and RAAS and their associated risks analyzed in term of genetic variants.

#### **2. Diabetes**

Diabetes is a global epidemic affecting people of both the developed and developing world. According to International Diabetes Federation, 9.3% of the world population had diabetes in 2019 and predicted that by 2045 about 10.9% of the world population may suffer from diabetes [7]. Prevalence of diabetes is increasing both in developing and developed countries. About 79% of the diabetic patients live in low-income or lower middle-income countries of which more than 60% belongs to Asian countries while rest of them are habitant of developed world [8]. Notably, diabetes is a health concern in adults compare to other age groups and it has been projected that between the years 2010 to 2030, developing countries will harbor 69% more adults with diabetes while 20% more adults with diabetes will be residing in developed countries [9]. Persistent elevated levels of plasma glucose result in long-term impediments of diabetes that cause macrovascular complications including CVDs, peripheral vascular disease, stroke and microvascular complications including nephropathy that leads to end-stage renal disease, retinopathy leading to blindness, neuropathy that causes damage to the nerves [2].

Diabetes can be classified into the following types [10]:


Of the major types, T2DM is the commonest form. T2D was caused by developing insulin resistance due to lifestyle, obesity, reduced physical activity [3]. Individuals with T2DM will have seven to ten years shorter life span compare to non-diabetic individuals and 80% patients with T2DM develop cardiovascular disease [11]. CVD like coronary artery disease is responsible for the 2–4 fold

#### *Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics DOI: http://dx.doi.org/10.5772/intechopen.97518*

increased rate of death in adults [12, 13]. Diabetes being considered as the independent risk factor from other such factors as age, gender, smoking, weight for dying from liver disease, lung disease, cancer, mental disorders, cardiovascular complications [14]. Moreover, people are more prone to infections or infectious diseases who have already developed diabetes [15] due to high levels of glucose in blood that favors immune dysfunction by modulating both innate (alteration of neutrophil functions) and adaptive (reducing T cell response) immune response [16–20]. Most recent incidence of pandemic has revealed that the severity of COVID-19 exaggerates in individuals with hyperglycemia due to augmented production of pro-inflammatory cytokines as well as poor innate immunity [21]. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection severely affects the survival rate of the infected individuals [21] with diabetes as it is a critical comorbidity [22].

T2D is a multifactorial and polygenic diseases caused by the association of different risk alleles located on multiple genes. Environmental factors modulating gene–gene interaction and/or expression are believed to be contributing factor for the development of T2D. Thus, genetic variants associated with T2DM are not only important for prediction and prevention of the disease along with its associated complications, but also will facilitate early treatment as well as need-based bona fide management of the disease.

#### **3. Renin-angiotensin-aldosterone system**

RAAS is one of the multifaced systems, which maintains homeostasis of body fluids, electrolyte balance and thus, regulates blood pressure [3, 23, 24]. Renin, initially known as pressor hormone, is an aspartic protease and it's only known substrate is angiotensinogen (AGT) [25]. Angiotensin converting enzyme (ACE) is a peptidase that is mainly found in the capillaries of lung followed by endothelial and kidney epithelial cells in human [26]. The classical RAAS involves cleavage of AGT for release of a small decapeptide, angiotensin-I (Ang-I). The peptidase ACE then converts Ang-I into an octapeptide, angiotensin-II (Ang-II). RAAS activity is intrinsically high in the lung where ACE level is very high and thus, a major site of systemic Ang-II synthesis.

The Ang-II is the most potent hormone peptide that utilizes G-protein coupled receptors (GPCRs) called angiotensin type 1 and type 2 receptors (AT1R and AT2R) to mediate physiological functions. Ang-II facilitates vasoconstriction, cell proliferation, cell hypertrophy, anti-natriuresis, fibrosis, and atherosclerosis using AT1R [27] while, via AT2R, the peptide elicits vasodilation, anti-proliferation, antihypertrophy, anti-fibrosis, anti-thrombosis, and anti-angiogenesis [28] (**Figure 1**). Ang-II also stimulates the production of the steroid hormone, aldosterone, which is the final product of the RAAS cascade. Aldosterone binds to the mineralocorticoid receptor and regulates the transcription of target genes, resulting in the upregulation of electrolyte flux pathways in the kidney. Dysregulation of RAAS can lead to adverse effects on fluid homeostasis, which in turn may lead to organ damage followed by CVDs.

Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE. ACE2 is also highly expressed in the lung. The main activity of ACE2 is to degrade Ang-II into angiotensin 1–7 (Ang 1–7) by hydrolyzing of the C-terminal residue [29]. Thus, ACE2, in the lung, have a role in adjusting the balance of circulating Ang-II/Ang 1–7 levels. Also, product of ACE2 facilitates vasodilation and therefore opposing the role of ACE product (i.e. Ang-II). Ang 1–7 is expected to exert its action through the MAS-related (MAS1) GPCR [30]. It is evident that insulin exhibits adverse effects

#### **Figure 1.**

*Renin-angiotensin-aldosterone system (RAAS) and its linkage to type 2 diabetes mellitus (T2DM). The classical RAAS shows angiotensin-II (Ang-II) dependent pathway mediated different physiological effects via G-protein coupled receptors (GPCR) called angiotensin type 1 and type 2 receptors (AT1R and AT2R). Renin, secreted from kidney, regulates the rate limiting step of this pathway by converting its liver originated substrate angiotensinogen (AGT) into a decapeptide, angiotensin-I (Ang-I). Ang-I is converted into an octapeptide Ang-II by angiotensin converting enzyme (ACE). Ang-II binds to AT1R and AT2R to mediate the counterbalanced physiological functions. Angiotensin converting enzyme 2 (ACE2) is to cleave Ang-II into angiotensin 1–7 (Ang 1–7), which exerts the vasodilation effects.*

on the structural and functional features of islet cells by inducing Ang-II mediated oxidative stress [31]. Through AT1R, Ang-II inhibits course of insulin action in vascular and skeletal muscle tissue, interferes insulin signaling via phosphatidylinositol 3-kinase and its downstream protein kinase B (Akt) signaling pathway [32].

Increased vasoconstriction and renal sodium reabsorption along with enhanced secretion of aldosterone results overactivation of RAAS followed by metabolic modulation leading to altered blood pressure and development of insulin resistance [33, 34]. Aldosterone has the ability to impair insulin signaling pathway by downregulating insulin receptor substrate-1 (IRS-1) in vascular smooth muscle cells [35] and thus, contributes to the development of and/or deteriorating metabolic disorders including disruption of glucose homeostasis [36].

The (pro)renin receptor [(P)RR], cloned almost two decades before in 2002 [37], has now been considered as one of the pivotal members of RAAS. Modulation of renin/prorenin takes place after binding to their receptor. After binding to (P) RR, the enzymatic activity of renin increases while the proactive form of renin known as prorenin gets activated non-proteolytically and exhibits renin activity [38, 39]. Binding to (P)RR with prorenin causes a change in conformation within the prosegment region followed by opening of the active site and making it accessible to the substrate, AGT [39, 40]. Thus, receptor mediated activity of renin and prorenin possibly activate tissue specific renin-angiotensin system in an Ang-II dependent manner, which ultimately could contribute in modulating local RAAS. (P)RR has been found to be ubiquitously expressed in brain, heart, placenta, liver, pancreas and kidney [37]. The association between *(P)RR* gene polymorphism and high blood pressure has been demonstrated in Caucasian and Japanese male subjects [41, 42]. In another study with transgenic rats over expressing (P)RR in smooth muscles it was reported to elevate blood pressure and increase heart rate in their models [43]. A single mutation in exon 4 of *(P)RR* gene is associated with mental

#### *Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics DOI: http://dx.doi.org/10.5772/intechopen.97518*

retardation and epilepsy [44] while a silent mutation in exon 4 on human (P)RR facilitates enhanced expression of c321C > T that lacked exon 4 [44]. Though presence of this single nucleotide polymorphism (SNP) does not bring any change as far as the renin binding ability is concerned but it modulates ERK1/2 activation [44], which may in turn modifies gene expression pattern.

RAAS mediates diverse functions by the action of angiotensin receptors (**Figure 1**) and has the link to cancer through tissue remodeling, inflammation, angiogenesis and apoptosis [45, 46]. Genetic and epidemiological studies showed that polymorphism of the RAS components contribute to the risk of cancer. Either the insertion/deletion (I/D) polymorphisms of *ACE* or *AGT* M235T SNP confer the risks for developing breast cancer [45]. Two *AT1R* SNPs are associated with risk for renal cell cancer, and its associations are stronger in subjects with hypertension [47]. Although the identified SNPs could be a marker of disease linked to another disease-causing SNP, rather than the disease-causing SNP itself [47], further studies are warranted to clarify cancer etiology involving the RAS components.

#### **4. Diabetes and RAAS**

Development of insulin resistance at the cellular level is initiated by Ang-II and aldosterone via increasing oxidative stress and altering insulin signaling (**Figure 2**). Ang-II is also responsible for generating pancreatic β-cell oriented oxidative stress, inflammation, and apoptosis. Evidence also suggested involvement of aldosterone in diminished glucose induced insulin secretion from pancreas [33].

The therapeutic approaches for lowering glucose levels significantly reduces the chance of developing diabetes associated microvascular complications while modest improvement has been observed in case of improving diabetes associated macrovascular complications [48, 49]. A case–control study conducted in German population demonstrated increased prevalence of T2D among individuals with hypertension and higher concentration of aldosterone (but low Ang-II level and low plasma renin activity) compared to the control hypertensive individuals [50].

#### **Figure 2.**

*Involvement of RAAS components into pathogenesis of T2DM. Hyperglycemia causes oxidative stress through generation of reactive oxygen species (ROS) that along with the production of Ang-II through overactive RAAS, may contribute to the pathophysiology of T2DM. Thus, genetic polymorphisms present in the genes expressing the components of RAAS probably modulate gene expression followed by protein levels that ultimately involve in the disease pathogenesis. Also, variants within these genes may also involve in the initiation and development of diabetes.*

Another study revealed association between higher levels of aldosterone and insulin resistance along with dose-dependent contribution of high aldosterone level to the risk of developing T2D [51]. **Figure 2** schematically represents components of RAAS involved in the regulation of physiology, and probable mechanism of their contribution to the pathophysiology of diabetes.

#### **5. T2DM and RAAS: contribution of the RAAS components to the pathogenesis of T2D**

The most important key features of the pathogenesis of diabetes are the resistance to insulin which in turn reduces the insulin ability to uptake peripheral glucose [52], and the failure of β-cells to produce adequate amount of insulin [53]. Obesity is one of the major risk factors for the development of insulin resistance along with sedentary lifestyle, lack of physical activities etc. that in turn increases the levels of glucose in blood [54]. Obesity is also involved in the activation of RAAS [55, 56]. On the other hand, RAAS has been found to be associated with multiple obesity-associated chronic diseases, especially for cardiovascular related disease [57, 58]. In addition, several lines of evidence revealed association between activation of RAAS and the onset of T2D [55, 59, 60]. The connection between renin angiotensin system and insulin signaling pathway along with insulin resistance has been established [61]. A meta-analysis demonstrated that use of AT1R blockers or ACE inhibitors reduces the chance of new onset of T2DM by 22% in a population who are vulnerable to diabetes [62]. Though association between *ACE* I/D polymorphisms and risk of T2D inconsistent even in the same population [63, 64], CAPP trial demonstrated that ACE inhibitor captopril-treated patient group had 11% reduced chance of developing diabetes compared to non-treated groups [65] while LIFE study showed 25% reduction in new onset of diabetes [66]. All together these studies strongly support linkage between RAS components and hyperglycemia. Moderate hyperglycemia at the early stage of diabetes results increased plasma renin activity, arterial pressure and renal vascular resistance with the activation of both local and circulating RAAS [67, 68]. Moreover, hyperglycemia causes glycosylation of p53 which leads to the AGT transcription followed by the production of Ang-II [69, 70]. This was further supported by Fiordaliso et al. who demonstrated a direct correlation among levels of glucose, p53 glycosylation and Ang-II production [71].

Genetic predisposition involving certain SNPs residing within the genes of RAAS has been anticipated as the risk factors for the development and progression of T2D and T2D associated complications hypertension [72], coronary heart disease [73], nephropathy [73–75] and retinopathy [76]. Human AGT, a member of serpin gene family, comprises of 5 exons accounting for a full-length of about 12 kb and is situated on chromosome 1 (1q42-q43). Most convincing evidence for the probable association of polymorphic sites within *AGT* gene with essential hypertension has been identified in the 5′ flanking region, exons, and introns of the gene [77]. Strong association of rs11568020 (A-152G) and rs5050 (A-20C) in the promoter region as well as rs4762 and rs699 within exon 2 of *AGT* gene with hypertension was evident in Eastern Indian population [72]. Interestingly, incompatible findings with respect to the association of *AGT* variants with T2D have been observed [62, 72, 78, 79]. Variants rs699 and rs4762 within *AGT* gene found to be associated with the reduced risk of T2D in Eastern Indian and Malaysian Malays populations [72, 78] while no significant association was observed in the Chinese and the Japanese populations [63, 79]. However, rs699, rs4762 and rs5051 of *AGT* gene were reported to be associated with the increased risk of T2DM in the Pakistani [80], Korean [81] and Malaysian Malays [78] populations, respectively.

#### *Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics DOI: http://dx.doi.org/10.5772/intechopen.97518*

It has been documented that Ang-II is capable of stimulating the production of TGF-β [82] or inducing generation of reactive oxygen species (ROS) [83] that causes over-accumulation of extracellular matrix proteins or various cellular dysfunctions in patients with diabetes. Furthermore, variants present within the genes of RAAS components especially within *ACE*, *AGT* and *AT1R* genes have shown to be the most promising candidate genes susceptible to diabetic associated complications like nephropathy along with its progression towards renal failure as well as retinopathy [78, 84]. Haplotype TCG of *AGT* has been observed to be associated with increased risk of T2D [78]. According to Purkait et al. [72], three haplotypes (H4, H7 and H8) of *AGT* showed strong association with hypertension while H2 had protective role against this disease. It is reported that the *AT1R* A1166C is not likely a risk factor for chronic kidney disease in East Asians and Caucasians while it is shown to be a risk factor in South Asian population [85, 86]. Almost 30–50% of the diabetic individuals are prone to develop kidney disease [87, 88]. Previous studies reported association of *renin* gene polymorphisms with number of noncommunicable diseases including diabetic nephropathy [89], increased risk of vascular complications [90], plasma renin activity [91], susceptibility to hypertension in a variety of ethnic groups [92–95], T2D [96] with inconsistent results [97–99]. Few studies did not find any significant association of *renin* rs16853055 with diabetes and diabetic nephropathy diseases [100, 101] while Purkait et al. [102] found an association of this variant with diabetic nephropathy in Indian population along with strong linkage disequilibrium with rs16853055. On the other hand, Deinum et al. reported weak association of *renin* gene polymorphism present in the first intron (involved in the regulation of transcription of renin) with diabetic nephropathy [89, 103]. Moreover, rs1799998 of the *CYP11B2* gene (aldosterone synthase) was associated with the levels of serum aldosterone and production [104, 105], blood pressure [106, 107], ischemic stroke [108], with the progression of renal function [109, 110] and end stage renal disease [111]. Meta-analysis performed by Xu et al. demonstrated association of allelic frequency as well as co-dominant homozygous and recessive models of inheritance with regard to −344 T/C polymorphism within promoter region of *CYP11B2* gene with the increased risk of diabetic nephropathy [112]. Similar association was observed by Purkait et al. [113] in Indian population. Promoter regions play important regulatory roles in gene transcription followed by formation of a functional protein through translation. Thus, presence of variants within the promoter region may be involved in the disease progression or pathogenicity which is definitely subject to further investigation and validation. Furthermore, methylation within the promoter region of a gene contributes to the expression of that particular gene [114]. Variant rs1799998 causes substitution of cytosine to thymidine within the promoter region of *CYP11B2* gene which is the binding site of a putative steroidogenic transcription factor-1 [115].

#### **6. Pathophysiology and genetics of type 2 diabetes**

Both environmental and genetic factors play pivotal role in the development of diabetes in human. However, some individuals develop diabetes while others do not although they use to live in the same environment. A substantial proportion of Pima Indians develop T2D even with a normal lifestyle in a normal environment that showed strong linkage of genetic make-up to T2D [116]. Thus, understanding genetics related to the pathogenesis of T2D is of utmost importance for the management of this global endemic disease. Familial studies orchestrated more robust data as proof that genes play important role as risk factor for the development of diabetes. First degree individuals with family history of T2D are at 3-fold increased risk of developing T2D compared to those who do not have positive family history [117–119]. Studies with monozygotic twins demonstrated that 50% risk of developing type 1 diabetes is contributed by *HLA* genes while rest of the 50% is associated with environmental factors and epigenetic modifications [120, 121]. Several family, population and twin-based studies established that heritability of T2D ranges from 20–80% [122, 123]. Forty percent individuals possess risk of developing T2D who have one parent with T2D while 70% of the individuals have higher risk of developing T2D if both the parents are T2D [124]. Seventy percent of monozygotic twins are in concordance with the chance of developing T2D while the concordance rate in dizygotic twins has been found to be 20–30% [125, 126].

The primary method to identify genes susceptible to T2D was genome linkage analysis. This approach efficiently identified causal mutations specially for the monogenic forms of diabetes like maturity-onset diabetes in young (MODY), mitochondrial diabetes in neonates and insulin resistance [127–129]. This approach further recognized the short tandem repeats located on q arm of chromosomes 4, 5, 10, 12, 22 and p arm of chromosomes 2, 3, 6, 13 for their probable association with T2D in different ethnic populations [130–134] along with causative genetic variants within *calpain10* (*CAPN10*) [135], *ENPP1* [136], *HNF4A* [137, 138] and *ACDC* [139]. Calcium-activated neutral protease 10, one of the regulator of glucose homeostasis, gene (*CAPN10*) variants UCSNP-43 G/A in intron 3, UCSNP-19 2R (two 32-bp repeats)/3R (three 32-bp repeats) in intron 6 and UCSNP-63 C/T in intron 13 have been reported to be associated with T2D in Mexicans Americans, German and Finnish populations [135, 140]. The ectonucleotide pyrophosphatase phosphodiesterase (ENPP1) was supposed to be associated with insulin resistance [141]. The three-alleles risk haplotype (K121Q/IVS20 delT-11/A > G + 1044 TGA, QdelTG) within ENPP1 was associated with childhood obesity, development of T2D and with adult obesity [136]. HNF4A, member of the steroid hormone receptor superfamily, plays major role in insulin expression and secretion followed by glucose metabolism in pancreatic β-cells along with gluconeogenesis in liver [142, 143]. Variants within *HNF4A* gene were identified as the risk factor for MODY and causative factor for β-cell dysfunctions [144]. Also, non-coding variants rs4812829 and rs6017317 as well as coding variant rs1800961 (T130I) within *HNF4A* were involved in the development of T2D [145–147]. Decreased level of adipose tissue-derived adiponectin in plasma is evident in individuals with obesity [148], insulin resistance [149] and T2D [148]. Adiponectin encoding *ACDC* gene variants 276G > T and 45 T > G were found to be associated with lower levels of plasma adiponectin in Japanese [150] and German obese people [151], respectively along with their predisposition to T2D. However, genome wide linkage analyses did not reveal any association of these variants of *ACDC* gene with obesity and T2D in Pima Indians [139]. Transcription factor TCF7L2 showed strongest linkage to the risk of T2D before genome wide association study (GWAS) era [130]. TCF7L2 involves in Wnt signaling pathway that regulates proliferation and survival of pancreatic islet cell functions [152] and its reduced expression is linked to impaired insulin secretion [153]. *TCF7L2* gene variants rs12255372 and rs7903146, showed strong linkage disequilibrium with composite at-risk alleles of the microsatellite marker (DG10S478).

Candidate gene association studies have also been proved to be effective to obtain substantial evidences of genetic predisposition to T2D. For example, insulinlike growth factor 2 mRNA-binding protein 2 (IGF2BP2), an important candidate gene for T2D [154, 155], was involved with T2D development by reducing insulin secretion [156] may be through changing adipose tissue and β-cell function [157]. IGF2BP2 was also associated with overweight and obesity [158]. Association of rs4402960 and rs1470579 within *IGF2BP2* with the risk of T2D demonstrated in French Caucasians while another study revealed that T2D patients carrying the

#### *Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics DOI: http://dx.doi.org/10.5772/intechopen.97518*

T allele of rs4402960 had higher levels of fasting plasma glucose, postprandial glucose, total cholesterol and postprandial serum insulin compared to individuals with the GG genotype [158]. Besides, *IGF2BP2* variants showed effect on treatment of diabetes. For example, lower efficacy of the repaglinide treatment for reducing fasting plasma glucose and postprandial glucose was observed in diabetic patients with rs1470579 AC + CC genotypes compared to AA genotypes. On the other hand, repaglinide treatment had higher effect on diabetic patients with GT + TT genotypes with regard to rs4402960 on postprandial insulin compared to GG genotype carrying patients [158]. The potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) has attracted attention due to its contribution to the pathogenesis of T2D by modulating insulin production and secretion [159] and thus, is a good candidate gene to elucidate its disease association. *KCNJ11* harboring four missense SNPs rs5219, rs1800467, rs5215, rs41282930 were recognized to influence risk of T2D by impairing insulin secretion [160]. Peroxisome proliferator activator receptor gamma (PPARG) was identified to harbor T2D disease susceptibility variants. Both *KCNJ11* and *PPARG* encode anti-diabetic drug targets and their respective missense SNPs rs5219 (E23K) and rs1801282 (P12A) are associated with the risk of T2D [161].

Although candidate gene and linkage analyses provided considerable evidences behind the genes for their probable association with the pathophysiology of T2D and/or with the risk of T2D, novel genes are yet demanding due to the inconsistent and discordant findings within the same population and also, in different ethnic groups. Screening of whole genome using GWAS helps to overcome the shortcomings of the above mentioned approaches to some extent by expediting regularly spaced variants without any prior knowledge of gene or their effects that has brought a significant breakthrough in understanding the genetic basis of T2D. This has become realistic after successful completion of the Human Genome Project and the International HapMap Project. This has given an opportunity to deposit millions of SNPs in the public databases [162] and presence of higher frequency of a particular SNP in cases compare to controls suggests association of that SNP with the case i.e., disease. Moreover, to satisfy association of SNPs statistically, stringent p value (<10−8) is required in GWAS and it benefited researchers to eliminate false positive association out of the millions of reported SNPs [163]. Even with such strict threshold levels of statistics, several case–control studies in different ethnicities have generated replicative positive results through different independent datasets. T2D associated variants within genes uncovered by GWAS positioned at different chromosomal locations (**Figure 3A**) can be grouped into i) insulin secretion and processing related (*GIPR*, *CCND2*, *CDKAL1*, *GCK*, *TCF7L2*, *GLIS3*, *THADA*, *IGF2BP2*, *DGKB*)*,* ii) impaired insulin function related *(PPARG, KLF14, IRS1),*  iii) insulin resistance related (*ACDC, FTO, KLF14, DUSP9*), iv) β-cell mass and function related (*IGF2BP2, HCNQ1, CDKN2A, CDKN2B*) and iii) body mass index (BMI) and lipid level related (*NRXN3, CMIP, APOE, and* MC4R)*.* Notably rs4731702 of intronless *KLF14* demonstrated an association with insulin resistance [164] while rs972283 contributed to elevated blood pressure [165], which may ultimately increase risk of cardiovascular disease; C allele of the rs2283228 within *HCNQ1* showed association with increased fasting glucose levels and impaired β-cell function in Asians [166], while C allele of rs2237895 in *KCNQ1* was found to be related to decreased risk of abdominal obesity in patients with T2DM [167, 168]; rs5945326 of *DUSP9* on X chromosome was related to the increased risk of T2D in Japanese [169], Pakistanis [170] and in European [171] populations; rs1558902 within *FTO* showed correlation with the incidence T2D in humans even after adjusting the data with confounding factors such as age and BMI [172] and rs9939609 may modulate the risk of T2D by regulating other genes, an incidence

#### **Figure 3.**

*Chromosomal locations of genes carrying variants (A) associated with* β*-cell function followed by insulin production and secretion (B), glucose utilization and homeostasis (C) along with glycemic traits and abnormal adipose tissue function (D) which all together may lead to T2D and of genes of major RAAS components. Several approaches specially GWASs identified several variants associated with pancreatic islet cell function followed by* β*-cell dysfunction, insulin secretion and processing (*red*), with development of insulin resistance followed by imbalanced glucose homeostasis (*blue*). Other variants are also associated with abnormal adipose tissue function which may also be caused by oxidative stress, a consequence of Ang-II (Figure 2). Variants within SLC30A8 and (P)RR (*green*) showed both protection against T2D and risk association with T2D as well as hypertension, respectively. Also, mostly non-coding and few coding variants within the genes (*black*) showed association with the risk of T2D. Variants within the major gene of RAAS have been found to be associated with the risk of T2D and T2D-associated hypertension other that their established risk association with essential hypertension and cardiovascular diseases. REN, renin; AGT, angiotensinogen; AT1R and AT2R, angiotensin type 1 and type 2 receptors, ACE, angiotensin converting enzyme; ACE2, angiotensin converting enzyme 2; CYP11B2, aldosterone synthase; (P)RR, (pro)renin receptor; In, insulin; Glc, glucose; IRS, insulin receptor substrate.*

independent of BMI [173]; variants present within the tumor suppressor cyclin dependent kinase inhibitors, CDKN2A and CDKN2B, reported to be associated with T2D in Asians and Europeans [174–177]. rs10811661 of CDKN2A/2B is also, according to GWAS, linked to diabetes [178]; hematopoietically-expressed homeobox or *HHEX* gene variants rs11118745G/A, rs7923837A/G, and rs5015480C/T had been identified as risk factors for T2D in Japanese [179], German [180], Korean [181], Indian [182] populations. Association of a common variant, Trp325Arg within *SLC30A8*, with the risk of T2D [171, 183]

*Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics DOI: http://dx.doi.org/10.5772/intechopen.97518*

and, levels of glucose [184] and proinsulin [185] had been well documented. Interestingly, through genotyping of ~150,000 individuals from five ethic groups, Flannick et al. (2014) revealed protective role against the development of T2D mediated by the loss of function variants harbored within *SLC30A8* [186]. AA genotype of rs11558471 of *SLC30A8* was found significantly more frequent in T2D patients than in controls in Han Chinese [187] and Indian [182] populations.

Non-coding variants within different genes [like variants of *PRC1,* MADD, *MTNR1B,* FADS1, CRY2, *GLIS3, LC2A2*, *ADCY5,* GCKR, G6CP2 [184], *TP53INP1*  [188], *GIPR* [189]*, ADCY5* [189]*, TSPAN8/LGR5, JAZF1,* Notch1 [190]*, HNF1B*  [191], *FTO* [155], *ZEDB3* [188]], as presented in **Figure 3A**, were also recognized as major risk factors associated with the development of T2D and/or regulation of glucose/insulin homeostasis, and/or glycemic traits (**Figure 3B** and **C**) and abnormal adipose tissue function (**Figure 3D**) while few variants were discerned to have protective roles against the development of diabetes [184, 188–195]. Also, similar association was found with regard to intergenic variants rs972283 (G/A, 47 kb upstream) of *KLF14* [188], rs2943641 (C/T, 502 kb upstream) of *IRS-1* [155], rs1111875 (C/T, 7.7 kb downstream) of *HHEX* [183], rs10811661 (T/C, 125 kb upstream) of *CDKN2A/2B [190],* rs4607103 (C/T, 38 kb upstream) of *ADAMSTS9* [190]*, regulatory region variant* rs5945326 (G/A, 8 kb upstream) of *DUSP9* [188], rs2191349 (T/G) of *DGKB/TMEM195* [196], promoter region rs2853669 of human telomerase reverse transcriptase (*TERT*) gene [197]*.* Noncoding variants positioned at essential regions like enhancer and promoter sequence may also modulate chromatin loops, alter sequence motifs and modulate histone marks that ultimately regulate gene expression, which could be one of the key reasons their disease association.

#### **7. Pathogenesis and genetics of RAAS**

RAAS is the enzymatic cascade to produce the effector molecule, Ang-II, by the multiple enzymes [23] (**Figure 1**). Various genotypes of the RAAS components [eg*.* AGT, renin, ACE, ACE2, AT1R, AT2R and (P)RR] have been investigated to find the link between genetic variation, blood pressure, and hypertension [198].

The two *AGT* genotypes (G-6A non-coding SNP and M235T coding SNP) are associated with higher plasma AGT levels and increased risks of essential hypertension [77]. The *AGT* SNPs occurring within the non-coding region could explain the association with plasma AGT concentration because of the alternation in AGT transcription [198]. It is plausible that the higher AGT concentration brings about the higher levels of Ang-II, which may lead to high blood pressure. In the study of 10,690 individuals, the associations of elevated blood pressure, ischemic heart disease and ischemic cerebrovascular disease were examined with four AGT variants (A-20C and G-6A non-coding SNPs and T174M and M235T coding SNPs) [199]. Both women and men with -6AA, 174TT, and 235TT (versus -6GG, 174TT, and 235TT) had higher mean levels of plasma AGT (861 ng/mL and 811 ng/mL, respectively). This finding suggests that the genotype has an effect on risk of elevated blood pressure in women, but not in men [199]. The association of the genotype with ischemic heart disease and ischemic cerebrovascular disease seems weak as a risk [199]. A meta-analysis of 45,267 individuals from different ethnic populations shows that M235T genotype is associated with an increase in plasma AGT levels [200]. An analysis of 424 individuals from 41 two-generation families from Utah indicates significant linkage between six *AGT* SNPs (rs5051, rs699, rs6687360, rs2478543, rs3789670 and rs943580) and plasma AGT levels whereas plasma AGT and blood pressure were not significantly correlated [201]. *AGT* SNPs have been

identified from various ethnic groups to show its association with hypertension [72, 202–205]. Of note, *AGT* genotypes (G-6A, T + 31C and M235T) with hypertension are not associated with plasma AGT level, while -1074 t|T235 haplotype is associated with an increase of AGT level but not with hypertension [202]. Sato et al. [202] suggested that the positive association between *AGT* polymorphism and hypertension is not simply explained by an increase of plasma AGT concentration.

Renin polymorphism was investigated by assessing the association of ten *renin* genotypes with hypertension risk in 570 hypertensive and 222 normotensive Caucasians [95]. Subjects with DM, secondary hypertension, significant medical illness or severe obesity were excluded, and their food intakes were also controlled. The A allele of rs6693954 SNP and the haplotype containing rs6693954A were significantly associated with higher risk of hypertension [95]. Compared to other haplotypes, the same haplotype showed the higher levels of plasma renin activity, suggesting that a direct renin inhibitor is effective to reduce blood pressure of rs6693954A carriers [95]. In addition, the haplotype displayed a blunted mean arterial pressure response to exogenously infused Ang-II [95], which infers the dysregulation of RAAS at the tissue level [206]. This study [95] confirms the association between *renin* genotypes and risk for hypertension.

As described above, genetic variations in individual RAAS components can contribute to the onset of physiological outcomes, which probably brings about the increase in blood pressure. But hypertension is a multifactorial disease involving both genetic and environmental factors [207] like T2D. The mechanism of susceptibility to hypertension and CVD is much more complex, since various genes work in an additive or interactive manner, together with environmental factors [198]. Ji et al. [205] provided the experimental evidence to support the idea. In a study of 905 hypertensive and 905 normotensive Han Chinese population, 41 SNPs of the five RAAS components (AGT, renin, ACE, AT1R, and CYP11B2) and the non-genetic factors were analyzed to investigate their associations with essential hypertension [205]. Subjects with CVD, DM, kidney diseases, secondary hypertension and other major chronic illnesses were excluded. Serum levels of total cholesterol and triglyceride, and BMI were significantly higher in the hypertensive group than in the normotensive group. Six SNPs (rs3789678 and rs2493132 within *AGT*, rs4305 within *ACE*, rs275645 within *AT1R*, rs3802230 and rs10086846 within *CYP11B2*) were shown to associate with hypertension. The interaction between BMI and rs4305 (*ACE* SNPs) increased the susceptibility to hypertension. Together with non-genetic factors, the genetic variations in the RAAS components may play an important role in determining an individual's susceptibility to hypertension [205].

GWAS analysis performed by Ji et al. [208] provided one important viewpoint on genetic polymorphism of RAAS. The authors searched GWAS Catalog (https:// www.ebi.ac.uk/gwas/) and identified all known RAAS genes and relevant diseases and traits. Remarkably, SNPs within *AGT*, *renin*, *ACE2*, *CYP11B2*, *ATP6AP2* [(*P) RR*] and *HSD11B2* were not associated with any disease and trait. There were SNPs being associated with other disease and trait: *ACE* (metabolic traits), *AT1R* (leads levels in blood), *AT2R* (fibrosis), *MAS1* (lipoprotein levels), *RENBP* (schizophrenia) and *NR3C2* (thyroid function). But these six SNPs showed no direct association with hypertension. The only SNP associated with a blood pressure trait was rs17367504, which is located in the intronic region of methylenetetrahydrofolate reductase (*MTHFR*) gene near many plausible candidate genes, including ion channel *CLCN*6, natriuretic peptides *NPPA* and *NPPB*, and RAAS component *AGTRAP*. The authored emphasized that the contribution of RAAS variants needs to be reconsidered when evaluating one's susceptibility of hypertension [208]. GWAS analysis is providing a new dimension for understanding genetic architecture of blood pressure and Page's "mosaic theory" of hypertension [209].

#### *Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics DOI: http://dx.doi.org/10.5772/intechopen.97518*

SARS-CoV-2 has emerged in December 2019, which caused COVID-19. The SARS-CoV-2 spike protein directly binds to ACE2, which is present on lung epithelial cells and other tissues [210]. ACE2 converts Ang-II to Ang 1–7 leading to tissue repair signal (**Figure 1**). When SARS-CoV-2 is attached to ACE2, it likely reduces the ACE2 activity associated with reduced inflammation, thereby increasing lung injury due to the decrease in Ang 1–7 generation [210]. It was observed that the severe COVID-19 patients are likely to have a history of diabetes, hypertension or CVD [5, 6]. For reducing the infection by COVID-19 and the other coronaviruses, deciphering the susceptibility to hypertension in term of genetic variations should be indispensable, which will be achieved by steady efforts to clarify the genetic background of each ethnic.

We recently reported probable association of five non-coding SNPs within *renin* and *(P)RR* genes with T2D, hypertension and T2D-associated hypertension in Bangladeshi population [211]. *Renin* SNP rs3730102 was associated with an increased risk of the three diseases. *Renin* SNP rs11571079 was associated with an increased risk for hypertension and T2D-associated hypertension, while the SNP showed a decreased risk for T2D, exerting a protective effect. *(P)RR* rs2968915|rs3112298 haplotypes were related to an increased risk of T2D and T2Dassociated hypertension. These findings highlight important roles of non-coding variants of *renin* and *(P)RR* genes in the etiology of several polygenic diseases [211]. Although there is a limitation for genotyping the candidate SNPs for the disease risk prediction, finding the candidate gene in different ethnic group through "oneto-one" approach should be valuable to design a measure for ensuring health and quality of life at all ages in each population group.

#### **8. Conclusion**

Though several studies have revealed genetic approaches to identify the pathophysiology of diabetes, hypertension and/or diabetes associated complications, it is still very challenging to uncover a definite candidate for the genetic etiology of these diseases due to overlapping involvement of genes, loci or even SNPs. GWASs have come forward to get rid of this elusiveness through scanning of whole genome. However, it is still very challenging due to the ethnic variations and ethnicitydependent gene expression patterns even harboring the same loci and/or variants to recognize genetic risk factors. Rather panels of variants (panels of variants for more closely related to T2D, panels for more closely related to hypertension and panels of overlapping variants in case of T2D and hypertension) could be a more meticulously related suggestive diagnostic, predictive and prognostic biomarker for these diseases. Known variants along with their gene expression pattern may play a pivotal role in determining disease pathogenesis.

#### **Acknowledgements**

We are grateful to all the members of Laboratory of Population Genetics, University of Dhaka as well as Biological Chemistry Laboratory and Biomolecular Chemistry Laboratory, Gifu University for their valuable suggestions and support. This work was supported in part by the JSPS KAKENHI (Grant No. 15 K01707 and 18KK0273).

#### **Conflict of interest**

The authors declare no competing interests.

### **Abbreviations**


*Diabetes and Renin-Angiotensin-Aldosterone System: Pathophysiology and Genetics DOI: http://dx.doi.org/10.5772/intechopen.97518*

### **Author details**

A.H.M. Nurun Nabi1,2 and Akio Ebihara3,4,5\*

1 Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh

2 United Graduate School of Agricultural Sciences, Gifu University, Gifu, Japan

3 Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan

4 Center for Highly Advanced Integration of Nano and Life Sciences, Gifu University (G-CHAIN), Gifu, Japan

5 Department of Chemical Engineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

\*Address all correspondence to: aebihara@gifu-u.ac.jp

© 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 2
