Role Of Ra Signaling In The Regulation Of The Reninangiotensin System

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1. Renin-Angiotensin System

The renin-angiotensin system (RAS) is a regulatory cascade that is critical for the maintenance of blood pressure, electrolyte, and volume homeostasis. Inappropriate stimulation of the RAS has been associated with hypertension, cardiac hypertrophy, myocardial infarction, and stroke. Ang II is the main effector molecule of the RAS (Bernstein and Berk, 1993). Renin, which is synthesized by the kidney and secreted into the blood, hydrolyses the dec-apeptide Ang I from the N-terminus of angiotensinogen. Ang I is converted to the octapeptide Ang II by the dipeptidyl carboxypeptidase, angiotensin-converting enzyme (ACE). Findings have shown that Ang II directly mediates cell growth, regulates gene expression, and activates multiple intracellular-signaling pathways in cardiovascular and renal cells (Baker and Aceto, 1990; Booz et al., 2002; Dostal et al., 1997; Schunkert et al., 1995). The importance of the RAS in cardiac remodeling is well documented. Numerous studies have shown that the RAS is activated in response to hemodynamic overload and that activation of the (local) RAS contributes to myocardial hypertrophy, fibrosis, and dysfunction (Cohn et al., 2000; Pfeffer et al., 1995; Schnee and Hsueh, 2000). In addition, animal studies (Kim et al., 2001; Nakamura et al., 2003) and clinical trials in humans (Cohn and Tognoni, 2001; Flather et al., 2000; Pfeffer et al., 2003) have shown that inhibition of Ang II by ACE inhibitors or AT1 receptor antagonists prevents or reverses ventricular remodeling and improves survival in patients with heart failure. ACE2 is a recently discovered homologue of ACE with tissue-restricted expression, including heart and kidney endothelium (Tipnis et al., 2000). ACE2 cleaves Ang I to generate Ang 1-9 and converts Ang II to Ang 1-7, a vasodilator (Donoghue et al., 2000; Ferrario et al., 1997). ACE2 has been implicated in heart function, hypertension, renal disease, and diabetes, with effects being mediated in part, through the ability to convert Ang II into Ang (1-7). Targeted disruption of ACE2 in the mouse results in a severe cardiac contractility defect, increased Ang II levels, and upregulation of hypoxia-induced genes in the heart, indicating that ACE2 is an essential regulator of heart function (Crackower et al., 2002). Studies have shown that Ang (1-7) acts as an endogenous inhibitor ofAng II, providing a negative feedback mechanism for the regulation of the actions of Ang II.

2. RA and the Renin-Angiotensin System

There is evidence that RA regulates the gene expression of RAS components, including renin, ACE, ACE2, and AT1 receptor. RA influences the renal RAS components in rats with experimental nephritis (Dechow et al., 2001). In the renal cortex of nephritic rats, pretreatment with RA significantly reduced mRNAs of all the examined renal RAS components (angiotensino-gen, renin, ACE, and AT1 receptor), but in glomeruli it increased ACE gene and protein expression. In vascular smooth muscle cells (VSMCs), RA dose-dependency inhibits Ang II-induced cell proliferation as well as DNA and protein synthesis. Ang II-induced gene expression of c-Fos and transforming growth factor-^ mRNA is abrogated by RA treatment. Downregu-lation of AT1 receptor mRNA and repressed Ang II-stimulated AT1 receptor promoter activity are observed in RA-treated VSMCs (Haxsen et al., 2001; Takeda et al., 2000). These findings demonstrate that retinoids are potent inhibitors of the actions of Ang II on VSMCs. It has been shown that RA downregulates the expression level of AT1, and upregulates the expression of ACE2 in the heart of SHR; but not in normal WKY rats (Zhong et al., 2004, 2005). Thus, RA-mediated signaling is involved in regulating RAS components during the development of hypertension. Further studies are necessary to elucidate the molecular mechanisms of the effects of RA on AT1 and ACE2 expression and the reason for a different role in hypertensive and normotensive rats.

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