**2. Renin-angiotensin system**

The RAS is classically known as a circulatory system or hormone that regulates blood pressure and homeostasis of electrolytes and fluids. This classic study is originated from 1898 when Tiergersted and Bergman found that the kidney contained a pressor substance, through non-purified salt extracts, which was called renin. This discovery came only to attract attention with Goldblatt et al in the twentieth century in 1934 when they demonstrated that the constriction of the renal arteries producing persistent hypertension in dogs due to reduction in vascular area with a consequent increase in strength and blood pressure (Goldman and Gilman, 2007). Six years later he declared that the renin was actually a protein that acted on a substrate in plasma. The name of this substrate for 20 years was controversial, as two groups of researchers, one from Argentina and other U.S. called them differently. The first group was called the substrate of *hipertensin* and the second *angiotonin* until these names were changed to *angiotensin*, the true pressor material. The precursor of this peptide was called angiotensinogen. Therefore, the time had an idea this simplified system, Figure 1.

In the 50's has been identified two forms of angiotensin, respectively called of angiotensin I and II. The first would be a chain of 10 peptides, hence the term decapeptide. In contrast, the second would be formed by cleavage of two peptides of angiotensin I to form an octapeptide. This cleavage occurs through the participation of an enzyme located on the luminal surface of endothelial cells of vascular system known as Angiotensin Converting

Hypertension and Renin-Angiotensin System 87

after this process pro-renin is activated by an enzyme not yet characterized, but cleaves 43 amino acids of the aminoterminal tail, thereby generating active renin. The secretion of renin by the juxtaglomerular cells (CJG) is controlled mainly by three ways: two act locally in the kidney and third acts indirectly through the CNS that releases norepinephrine from noradrenergic nerves of the kidney. The macula densa is a mechanism that controls the release of renin. It is a complex mechanism that relies on receptors, cyclic adenosine monophosphate (cAMP) and also through prostaglandins. In general, the macula densa is located adjacent to the CJG and is composed of columnar epithelial cells. When any change occurs in the flow of NaCl present in the macula densa cells release chemical signals that the CJG will inhibit or stimulate renin in the event of an increase or reduction of NaCl respectively. These signals via macula is mediated by both adenosine and prostaglandin by the first of which operates in the increase of NaCl and the second reduction. Regardless of which protein will act (adenosine or prostaglandin), the fact is that the answer to these is through the binding of these G protein coupled receptors, which will promote a signal dependent on the cellular second messenger (cAMP). Thus while acting within the A1 adenosine receptor adenosine inhibits renin release, while the prostaglandin stimulates.

The second mechanism that controls the release of renin is intrarenal baroreceptor pathway. This mechanism is regulated by raising and lowering blood pressure in pre-glomerular vessels, and thus are regulated by mechanical phenomenon. This mechanical modulation causes CJG inhibit or stimulate the release of renin. Moreover, the increase or reduction in renal perfusion pressure may inhibit the release or renal prostaglandin which act in part via

Finally, the third mechanism is called via the beta-adrenergic receptors. In this case, regulation occurs via the CNS. After the release and action of this neurotransmitter norepinephrine from postganglionic sympathetic nerves occurs when it binds to betaadrenergic receptors stimulating the sympathetic pathway and consequently the secretion of

These three mechanisms of regulation of renin secretion are involved in a physiological

1. The increased release of renin leads to increased release of angiotensin II. This in turn binds to AT1 receptors in the CJG. This binding leads to inhibition of renin secretion in

2. In addition to angiotensin II also leads to an increase in blood pressure by binding these AT1 receptors. In increased pressure leads to a reduction in renin secretion through the action of high pressure baroreceptors, increased pressure from pre-glomerular vessels and reduced pressure natriuresis (drop in reabsorption of NaCl). This mechanism of reduction of renin secretion via increased blood pressure arising from the effects of

**Angiotensionogen:** It is important to a globular protein, has a (MW = 55,000 to 60,000) and is the main substrate of renin. The angiotensinogen is synthesized in the liver, although it may have also made their transcription in adipose tissue in the CNS and kidney. There is a very close relationship between the synthesis and secretion of angiotensinogen by stimuli such as inflammation, insulin, estrogens, glucocorticoids, thyroid hormone and angiotensin II, ie, all these stimuli increase the synthesis and secretion of dodecahydrate peptide. There

the intrarenal baroreceptor.

network, explained below:

a mechanism known as short feedback loop.

angiotensin II is known as negative feedback loop long.

renin by CJG.

Enzyme (ACE). In the overview of the peptide angiotensin II is more active, that is, angiotensin II that has the main vasoconstrictor effect. Thus by mid-50, the overall picture of this system was extended by both the description of the two angiotensins, and by the observation that this system RAS concurrently regulated secretion of aldosterone. Based on this knowledge that was acquired, the 70 and 80 was an improvement on the findings of these polypeptides that interfere with components of the RAS, is directly inhibiting the release of renin, or ACE, and angiotensin receptor antagonists. Anyway, these findings allow to the present day an increase in quality of life, these compounds being the main drug involved in the treatment of hypertension, congestive heart failure, diabetic nephropathy, myocardial infarction, more recent studies show the effects of these in inflammatory disorders. To understand this 'fine' relationship between RAS and inflammatory process, it is to reading the components of this system.

Fig. 1. Diagram showing the evolution in a simplified manner on the physiology of RAS. [Figure made by Barros, RS - 2011].

#### **3. Renin angiotensin system components**

**Renin:** It is the major protease able of determining the rate of production of angiotensin II. Renin is produced, stored and secreted in so-called juxtaglomerular cells, cells that are circulating in the renal artery, present in the afferent arterioles, ie, the infiltrating *glomerulus* in promoting renal perfusion in this region. The release of renin is done through a process called as exocytosis. The main substrate of this aspartyl protease is an α2 - globulin stock, ie, angiotensinogen that is secreted by hepatocytes. Regardless, the renin, which cleaves peptide bonds aminoterminal tail of the angiotensinogen (Leucyl-leucine in mice and rats) and (Leucine-valine in humans), leading to angiotensin I, is an active renin. Thus the synthesis of this protease is done in stages. The active form that contains 340 amino acids. It is synthesized as a pre-pro-enzyme with 406 amino acid residues, soon after, this precursor is processed and thus generates a pro-renin, which is a more mature, but no activity. Soon

Enzyme (ACE). In the overview of the peptide angiotensin II is more active, that is, angiotensin II that has the main vasoconstrictor effect. Thus by mid-50, the overall picture of this system was extended by both the description of the two angiotensins, and by the observation that this system RAS concurrently regulated secretion of aldosterone. Based on this knowledge that was acquired, the 70 and 80 was an improvement on the findings of these polypeptides that interfere with components of the RAS, is directly inhibiting the release of renin, or ACE, and angiotensin receptor antagonists. Anyway, these findings allow to the present day an increase in quality of life, these compounds being the main drug involved in the treatment of hypertension, congestive heart failure, diabetic nephropathy, myocardial infarction, more recent studies show the effects of these in inflammatory disorders. To understand this 'fine' relationship between RAS and inflammatory process, it

Fig. 1. Diagram showing the evolution in a simplified manner on the physiology of RAS.

**Renin:** It is the major protease able of determining the rate of production of angiotensin II. Renin is produced, stored and secreted in so-called juxtaglomerular cells, cells that are circulating in the renal artery, present in the afferent arterioles, ie, the infiltrating *glomerulus* in promoting renal perfusion in this region. The release of renin is done through a process called as exocytosis. The main substrate of this aspartyl protease is an α2 - globulin stock, ie, angiotensinogen that is secreted by hepatocytes. Regardless, the renin, which cleaves peptide bonds aminoterminal tail of the angiotensinogen (Leucyl-leucine in mice and rats) and (Leucine-valine in humans), leading to angiotensin I, is an active renin. Thus the synthesis of this protease is done in stages. The active form that contains 340 amino acids. It is synthesized as a pre-pro-enzyme with 406 amino acid residues, soon after, this precursor is processed and thus generates a pro-renin, which is a more mature, but no activity. Soon

is to reading the components of this system.

[Figure made by Barros, RS - 2011].

**3. Renin angiotensin system components** 

after this process pro-renin is activated by an enzyme not yet characterized, but cleaves 43 amino acids of the aminoterminal tail, thereby generating active renin. The secretion of renin by the juxtaglomerular cells (CJG) is controlled mainly by three ways: two act locally in the kidney and third acts indirectly through the CNS that releases norepinephrine from noradrenergic nerves of the kidney. The macula densa is a mechanism that controls the release of renin. It is a complex mechanism that relies on receptors, cyclic adenosine monophosphate (cAMP) and also through prostaglandins. In general, the macula densa is located adjacent to the CJG and is composed of columnar epithelial cells. When any change occurs in the flow of NaCl present in the macula densa cells release chemical signals that the CJG will inhibit or stimulate renin in the event of an increase or reduction of NaCl respectively. These signals via macula is mediated by both adenosine and prostaglandin by the first of which operates in the increase of NaCl and the second reduction. Regardless of which protein will act (adenosine or prostaglandin), the fact is that the answer to these is through the binding of these G protein coupled receptors, which will promote a signal dependent on the cellular second messenger (cAMP). Thus while acting within the A1 adenosine receptor adenosine inhibits renin release, while the prostaglandin stimulates.

The second mechanism that controls the release of renin is intrarenal baroreceptor pathway. This mechanism is regulated by raising and lowering blood pressure in pre-glomerular vessels, and thus are regulated by mechanical phenomenon. This mechanical modulation causes CJG inhibit or stimulate the release of renin. Moreover, the increase or reduction in renal perfusion pressure may inhibit the release or renal prostaglandin which act in part via the intrarenal baroreceptor.

Finally, the third mechanism is called via the beta-adrenergic receptors. In this case, regulation occurs via the CNS. After the release and action of this neurotransmitter norepinephrine from postganglionic sympathetic nerves occurs when it binds to betaadrenergic receptors stimulating the sympathetic pathway and consequently the secretion of renin by CJG.

These three mechanisms of regulation of renin secretion are involved in a physiological network, explained below:


**Angiotensionogen:** It is important to a globular protein, has a (MW = 55,000 to 60,000) and is the main substrate of renin. The angiotensinogen is synthesized in the liver, although it may have also made their transcription in adipose tissue in the CNS and kidney. There is a very close relationship between the synthesis and secretion of angiotensinogen by stimuli such as inflammation, insulin, estrogens, glucocorticoids, thyroid hormone and angiotensin II, ie, all these stimuli increase the synthesis and secretion of dodecahydrate peptide. There

Hypertension and Renin-Angiotensin System 89

angiotensin II on the pathophysiology of hypertension is the morphological alteration of the cardiovascular system, causing hypertrophy of cardiac and vascular cells, and increase the

As discussed previously classicaly, the rennin-angiotensin system (RAS) has been considered a hormonal circulating system. The so-called systemic or circulating RAS plays a crucial role in the maintenance of blood pressure and electrolyte as well as fuid homeostasis15. This is mediated through its constrictive actions on vascular smooth muscle and by its influence on aldosterone secretion from the adrenal cortex, electrolyte transport in kidney, and on thirst as well as sodium appetite in the brain. In addition to its actions on the cardiovascular, renal, and nervous system, the expression of local RAS components in tissues such as the brain, kidneys, adrenals and gonads has led to the proposition that these components may either potentate systemic functions, or have entirely separate activities meeting the specific needs of these individual tissues.There is accumulating evidence that changes in tissue/organ-specific RAS may be associated with the pathophysiology of the

The final goal of the RAS is the angiotensin II production that acts through the interaction with two pharmacologically defined receptor subtypes, namely type 1 (At1) and type 2 (At2) that are distributed in numerous target tissues and organs like pancreas, for example (Chan

Some studies show that AT1 and AT2 receptors when activated by angiotensin II may lead to tissue that expresses inflammatory responses develop. This is the case of acute pancreatitis, which expresses the receptor AT1a more significantly than the receiver AT1b. In contrast, the AT2 receptor is most often responsible for these inflammatory responses

The role of RAS in the inflammatory process was further evidenced by the ability of an ACE inhibitor to suppress inflammation and subsequent tissue injury (Pupilli et al., 1999). Some studies suggest that losartan, an At1 blocker, and lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, can inhibit both the liver fibrosis and portal hypertension occurring in secondary biliary cirrhosis by inhibiting hepatic stellate cells (HSCs) activation (Agarwal et al.,1993). Other studies in vitro of cultured pancreatic stellate cells have demonstrated that these cells exhibit morphological and functional features similar to cultured hepatic stellate cells, including positive SMA staining after a period of time in culture, increased proliferation in response to PDGF, and increased collagen synthesis in response to TGF-β (Gressner et al., 1995). So these stellate cells could trigger an inflammatory process in the

Although other tissues, these stellate cells can not express the AT1 and AT2 receptors are widely distributed throughout the system and this can lead to a local inflammatory response by angiotensin II signaling. Given this relationship, it is necessary to comment briefly on the

**ACE Inhibitors:** The essential effect of the agents belonging to this group of drugs is just the inhibition of the conversion of angiotensin I to II. In this respect ACE inhibitors are selective

mechanism of action of antihypertensive agents shown below.

synthesis and deposition of collagen by cardiac fibroblasts.

respective tissue/organ functions (Ip et al., 2003).

et al., 2000).

more pronounced.

tissue which is expressed.

**5. Antihypertensive drugs and its relationship to inflammation** 

is a strong relationship between the amount of circulating *angiotensinogen* in plasma and increased blood pressure, so the use of oral contraceptives containing estrogen lead to an increase in serum angiotensinogen, thereby resulting in an elevation of blood pressure. At this point becomes more clear also the strong relationship with the inflammatory process. We have seen that directly interferes with the prostaglandin release of renin, ie, prostaglandins increase the secretion of this hormone by binding to adenosine receptors.

**Angiotensin Converting Enzyme (ACE):** ACE is a glycoprotein ecto-enzyme and that in addition to cleaving angiotensin I to angiotensin II forming this ecto-enzyme can also inactivate bradykinin, because ACE is very nonspecific and can cleave dipeptide units with many amino acid substrate. Therefore, the ACE inhibitors such as captopril and lisinopril, for example, are able to increase bradykinin and reduce angiotensin II. The rapid in vivo conversion of angiotensin I to II occurs through the action of ACE that is present on the luminal surface of endothelial cells throughout the vascular system. In addition to these effects of ACE some studies show the existence of a carboxypeptidase-related enzyme called ACE2 is capable of cleaving angiotensin I into (angiotensin 1-9) and angiotensin II (angiotensin 1-7). This enzyme is not inhibited by classic ACE inhibitors. Its physiological importance is not yet clear.
