How well do aliskiren's purported mechanisms track its effects on cardiovascular and renal disorders?

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• 作者：Gowraganahalli Jagadeesh^a ; ¹ ; ^{Gowra.Jagadeesh@fda.hhs.gov} ; Pitchai Balakumar^b ; ^{pbala2006@gmail.com} ; Norman Stockbridge^a ; ¹ ; ^{Norman.Stockbridge@fda.hhs.gov}
• 关键词：ACE ; angiotensin converting enzyme ; Ang-II ; angiotensin-II ; Aog ; angiotensinogen ; ARB ; Ang-II type 1 (AT1) receptor blocker ; eNOS ; endothelial nitric oxide synthase ; HCTZ ; hydrochlorothiazide ; HRP ; handle region peptide ; JNK ; c-Jun-N-terminal kinase ; MAPK
• 刊名：Cellular Signalling
• 出版年：2012
• 期刊代码：42_08986568
• 类别：bio
• 出版时间：August, 2012
• 卷：24
• 期：8
• 页码：1583-1591
• 文件大小：621 K

摘要

The overactivation of the renin-angiotensin-aldosterone system (RAAS) is associated with cardiovascular and renal abnormalities, which can be mitigated by angiotensin converting enzyme inhibitors (ACEIs) and angiotensin-II (Ang-II)-AT₁ receptor blockers (ARBs). Both prorenin and renin bind to the (pro)renin receptor (PRR) to activate Ang-II-dependent and -independent signaling cascades. Renin cleaves angiotensinogen to Ang-I, which is subsequently converted into Ang-II leading to cardiovascular and renal compensatory responses and eventually dysfunction. This initial step is blocked by renin inhibitor aliskiren, thus explaining its anti-hypertensive effect. Aliskiren is approved for the treatment of hypertension either as monotherapy or in combination with amlodipine, hydrochlorothiazide, or valsartan. Several clinical trials have suggested an organoprotective potential of aliskiren beyond its anti-hypertensive action, but the mechanism by which this might occur is less clear. Like ACEIs and ARBs, aliskiren increases plasma renin concentration; however, aliskiren reduces plasma renin activity. Intriguingly, aliskiren has additional abilities to downregulate the expression of the PRR and the AT₁ receptor, adding novel mechanistic insights to our current knowledge. Importantly, a few questions remain unresolved, such as the potential effects of aliskiren on (i) prorenin and its receptor-mediated Ang-II-independent pathways, and (ii) the signal network that comprises of PRR-associated vacuolar-H⁺-ATPase-linked Wnt/Frizzled signal transduction, including canonical-尾-catenin and non-canonical Wnt-JNK-Ca^2 + signals. Discrepant outcomes in ALTITUDE study make more complex understanding aliskiren's therapeutic potential in treating cardio-renal disorders. This review attempts to address some of the remaining questions regarding aliskiren's action in cardiovascular and renal disorders.