Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
Pflugers Arch. 2013 Jan;465(1):87-97. doi: 10.1007/s00424-012-1105-z. Epub 2012 Apr 28.
The discovery of a (pro)renin receptor ((P)RR) in 2002 provided a long-sought explanation for tissue renin-angiotensin system (RAS) activity and a function for circulating prorenin, the inactive precursor of renin, in end-organ damage. Binding of renin and prorenin (referred to as (pro)renin) to the (P)RR increases angiotensin I formation and induces intracellular signalling, resulting in the production of profibrotic factors. However, the (pro)renin concentrations required for intracellular signalling in vitro are several orders of magnitude above (patho)physiological plasma levels. Moreover, the phenotype of prorenin-overexpressing animals could be completely attributed to angiotensin generation, possibly even without the need for a receptor. The efficacy of the only available putative (pro)renin receptor blocker handle region peptide remains doubtful, leading to inconclusive results. The fact that, in contrast to other RAS components, (P)RR knock-outs, even tissue-specific, are lethal, points to an important, (pro)renin-independent, function of the (P)RR. Indeed, recent research has highlighted ancillary functions of the (P)RR as an essential accessory protein of the vacuolar-type H(+)-ATPase (V-ATPase), and in this role, it acts as an intermediate in Wnt signalling independent of (pro)renin. In conclusion, (pro)renin-dependent signalling is unlikely in non-(pro)renin synthesizing organs, and the (P)RR role in V-ATPase integrity and Wnt signalling may explain some, if not all of the phenotypes previously associated with (pro)renin-(P)RR interaction.
2002 年发现的（前）肾素受体（（P）RR）为组织肾素-血管紧张素系统（RAS）活性提供了长期寻求的解释，并为循环前肾素（肾素的无活性前体）在靶器官损伤中的作用提供了解释。肾素和前肾素（（前）肾素）与（P）RR 的结合增加了血管紧张素 I 的形成并诱导细胞内信号转导，导致产生促纤维化因子。然而，体外细胞内信号转导所需的（前）肾素浓度要高出（病理）生理血浆水平几个数量级。此外，（前）肾素过表达动物的表型可以完全归因于血管紧张素的产生，甚至可能不需要受体。唯一可用的假定（前）肾素受体阻滞剂处理区域肽的疗效仍然值得怀疑，导致结果不确定。与其他 RAS 成分不同的事实是，（P）RR 敲除体，即使是组织特异性的，都是致命的，这表明（P）RR 具有重要的、（前）肾素独立的功能。事实上，最近的研究强调了（P）RR 的辅助功能，作为液泡型 H(+)-ATP 酶（V-ATPase）的必需辅助蛋白，并且在这种作用中，它作为 Wnt 信号的中间物起作用，而与（前）肾素无关。总之，（前）肾素依赖性信号转导在非（前）肾素合成器官中不太可能发生，（P）RR 在 V-ATPase 完整性和 Wnt 信号转导中的作用可能解释了以前与（前）肾素-（P）RR 相互作用相关的一些（如果不是全部）表型。
