Signal transduction of the (pro)renin receptor as a novel therapeutic target for preventing end-organ damage

Abstract

The (pro)renin receptor ((P)RR) not only represents a novel component of the renin-angiotensin system but is also a promising novel drug target because of its crucial involvement in the pathogenesis of renal and cardiac end-organ damage. This review discusses the signal transduction of the (P)RR with its adapter protein promyelocytic zinc-finger protein, the impact of this receptor, especially on cardiovascular disease, and its putative interaction with renin inhibitors such as aliskiren. Furthermore, the increasing complexity regarding the cellular function of the (P)RR is addressed, which arises by the intimate link with proton pumps and the phosphatase PRL-1, as well as by the presence of different subcellular localizations and of a soluble isoform of the (P)RR. Finally, the rationale and strategy for the development of small-molecule antagonists of the (P)RR, called renin/ prorenin receptor blockers, are presented.

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

“…In cardiomyocytes, (pro)renin-bound (P)RR stimulates p38 MAPK, heat shock protein 27 and phosphatidylinositol-3-kinase-85. [89][90][91][92][93][94] Thus, diabetic nephropathy and retinopathy, and cardiac fibrosis develop mainly by the non-proteolytic activation of (pro)renin bound to the (P)RR. An upregulation in (pro)renin and (P)RR levels contributing to the development of nephropathy in diabetic animals has been reported by many investigators (reviewed in Balakumar and Jagadeesh 26 ).…”

Aliskiren affects fatty-acid uptake and lipid-related genes in rodent and human cardiomyocytes

“…The complexity of RAAS is evidenced by the discovery that binding of (pro)renin to the (pro)renin receptor ((P)RR) [28] can produce non-angiotensin-IImediated effects which are not inhibited by aliskiren [29][30][31]. This latter finding underpins the concept that renin can act not only as an enzyme but also as a hormone [10,20], providing a putative mechanism for non-blood-pressure-related effects of all three classes of RAAS inhibitor, and thus important insights into how to combine different RAAS inhibitors in tailored therapies [3,10,32]. Yet, only five studies to date [7,9,17,32,33] have focussed on the cellular or molecular mechanisms underlying organ protection by aliskiren, and none have directly investigated the role(s) that metabolism might play.…”

“…Some of the mechanisms by which these actions occur remain unclear, which highlights the increasing complexity of RAAS and especially the cellular function of (P)Rr [20]. Our study therefore raises fundamental questions for an emerging area of investigation into the metabolic effects of aliskiren and their relationship with organ protection and excitation-contraction coupling.…”

“…A recent report shows that aliskiren is able to reduce atherogenesis in mice independent of anti-hypertensive effects [16]. Second, aliskiren also appears to be functionally beneficial or protective in other tissues (pancreatic β-cell epithelium [17,18], white adipose [18], immune and nervous tissues [19]) and might even reverse end-organ damage [3,7,20]. Third, DRI appears to have haemodynamic effects, in spontaneously hypertensive rats [7], in healthy humans on a low-sodium diet [21], and in patients with congestive heart failure [22].…”

Effect of oxidized low-density lipoprotein on the expression of the prorenin receptor in human aortic smooth muscle cells

“…Numerous studies have verified that when the renin precursor binds to its receptor, it directly triggers angiotensin II independent reactions, which may be potentially active in the development of atherosclerotic plaques (14,15). The binding to PRR and the ability to induce a signal transduction cascade independent of the generation of angiotensin Ⅱ (13,16), including the activation of mitogen-activated protein kinase (MAPK) (17) and enhancement of the phosphorylation of extracellular signal-regulated kinase (ERK1/2) (18), promotes fibrosis gene expression, including transforming growth factor-β, plasminogen activator inhibitor-1, fibronectin and collagen proteins (19,20). However, to the best of our knowledge, there is little data demonstrating the direct effect of the atherogenic condition on the PRR.…”