(Pro)renin and its receptors: pathophysiological implications

Abstract

Tissue angiotensin generation depends on the uptake of circulating (kidney-derived) renin and/or its precursor prorenin [together denoted as (pro)renin]. Since tissue renin levels are usually somewhat higher than expected based upon the amount of (renin-containing) blood in tissue, an active uptake mechanism has been proposed. Several candidates have been evaluated in the past three decades, including a renin-binding protein, the mannose 6-phosphate/insulin-like growth factor II receptor and the (pro)renin receptor. Although the latter seemed the most promising, its nanomolar affinity for renin and prorenin is several orders of magnitude above their actual (picomolar) levels in blood, raising doubt on whether (pro)renin-(pro)renin receptor interaction will ever occur in vivo. A wide range of in vitro studies have now demonstrated (pro)renin-receptor-induced effects at nanomolar renin and prorenin concentrations, resulting in a profibrotic phenotype. In addition, beneficial in vivo effects of the putative (pro)renin receptor blocker HRP (handle region peptide) have been observed, particularly in diabetic animal models. Despite these encouraging results, many other studies have reported either no or even contrasting effects of HRP, and (pro)renin-receptor-knockout studies revealed lethal consequences that are (pro)renin-independent, most probably due to the fact that the (pro)renin receptor co-localizes with vacuolar H+-ATPase and possibly determines the stability of this vital enzyme. The present review summarizes all of the recent findings on the (pro)renin receptor and its blockade, and critically compares it with the other candidates that have been proposed to mediate (pro)renin uptake from blood. It ends with the conclusion that the (pro)renin-(pro)renin receptor interaction, if it occurs in vivo, is limited to (pro)renin-synthesizing organs such as the kidney.

Hypertension

“…One such candidate, the so-called (pro)renin receptor ((P)RR), which binds both renin and prorenin, has received much attention during the last decade. 5 Unfortunately, the concentrations of renin/prorenin (together denoted here as (pro)renin) that are required to result in receptor binding are far above the normal (patho)physiological levels, and transgenic rodents overexpressing either the (P)RR or prorenin did not reveal any evidence for (pro)renin-(P)RR interaction in vivo, that is, their Ang II levels were unaltered. 6 Moreover, (P)RR knockout (KO), unlike renin KO, is lethal.…”

“…Classically, interference occurs at the level of renin, angiotensin-converting enzyme (ACE), the Ang II type 1 (AT 1 ) receptor (R), or the mineralocorticoid receptor (MR), with renin inhibitors, ACE inhibitors AT 1 receptor blockers (ARBs) or MR antagonists. Novel enzyme inhibitors now target aminopeptidase A (APA), which generates Ang III (=Ang- [2][3][4][5][6][7][8]) from Ang II (=Ang-1-8)), or aldosterone synthase (CYP11B2). Activators of ACE2 (XNT and diminazene), which generates Ang-(1-7) from Ang II, were recently found to act equally well in ACE2 knockout (KO) animals, thus questioning their mechanism of action.…”

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

“…[2][3][4][5][6] However, the physiological relevance of the (pro)renin-(P)RR interaction is questionable because the (pro)renin concentrations required are >1000× higher than observed under (patho) physiological conditions. 7,8 Recently, (pro)renin-independent functions for (P)RR have been reported, including a function as an accessory protein of the vacuolar H + -ATPase (V-ATPase). 9 V-ATPases are multisubunit complexes, and they are expressed virtually in all cells types.…”

New role for the (pro)renin receptor in T-cell development

“…2 However, subsequent transgenic animal models failed to show a causal link between PRR and hypertension. [2][3][4][5] Instead, it has emerged that PRR is essential for cellular development and homeostasis. PRR is ubiquitously expressed, and total knockout in mice is embryonic lethal.…”

“…Disturbances in many processes have been observed upon deletion of PRR. 5,12 These effects appear to be central to the molecular association of PRR with the vacuolar (V)-adenosine triphosphatase (ATPase), where it is proposed that PRR regulates V-ATPase activity. 13 Much insight into PRR function has come from developmental biology studies, which showed that the association of PRR with the V-ATPase is essential for canonical Wnt signaling, 13 an important developmental pathway.…”