AstraZeneca-Shenzhen University Joint Institute of Nephrology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China; Erasmus Medical Center, Department of Internal Medicine, Division of Pharmacology and Vascular Medicine, Rotterdam, The Netherlands.
Erasmus Medical Center, Department of Internal Medicine, Division of Pharmacology and Vascular Medicine, Rotterdam, The Netherlands.
Pharmacol Res. 2017 Nov;125(Pt A):48-56. doi: 10.1016/j.phrs.2017.05.016. Epub 2017 May 19.
The discovery of the (pro)renin receptor [(P)RR] 15years ago stimulated ideas on prorenin being more than renin's inactive precursor. Indeed, binding of prorenin to the (P)RR induces a conformational change in the prorenin molecule, allowing it to display angiotensin-generating activity, and additionally results in intracellular signaling in an angiotensin-independent manner. However, the prorenin levels required to observe these angiotensin-dependent and -independent effects of the (P)RR are many orders above its in vivo concentrations, both under normal and pathological conditions. Given this requirement, the idea that the (P)RR has a function within the renin-angiotensin system (RAS) is now being abandoned. Instead, research is now focused on the (P)RR as an accessory protein of vacuolar H-ATPase (V-ATPase), potentially determining its integrity. Acting as an adaptor between Frizzled co-receptor LRP6 and V-ATPase, the (P)RR appears to be indispensable for Wnt/β-catenin signaling, thus explaining why (P)RR deletion (unlike renin deletion) is lethal even when restricted to specific cells, such as cardiomyocytes, podocytes and smooth muscle cells. Furthermore, recent studies suggest that the (P)RR may play important roles in lipoprotein metabolism and overall energy metabolism. In this review, we summarize the controversial RAS-related effects of the (P)RR, and critically review the novel non-RAS-related functions of the (P)RR, ending with a discussion on the potential of targeting the (P)RR to treat cardiovascular diseases.
15 年前，（前）肾素受体 [(P)RR] 的发现激发了人们的想法，即前肾素不仅仅是肾素的无活性前体。事实上，前肾素与 (P)RR 的结合诱导前肾素分子发生构象变化，使其能够表现出血管紧张素生成活性，并且以血管紧张素非依赖性方式导致细胞内信号转导。然而，观察到 (P)RR 的这些血管紧张素依赖性和非依赖性作用所需的前肾素水平比其在正常和病理条件下的体内浓度高出许多数量级。鉴于这一要求，(P)RR 在肾素-血管紧张素系统 (RAS) 中具有功能的想法现在正在被摒弃。相反，研究现在集中在 (P)RR 作为液泡 H+-ATP 酶 (V-ATPase) 的辅助蛋白上，可能决定其完整性。作为 Frizzled 共受体 LRP6 和 V-ATPase 之间的衔接蛋白，(P)RR 似乎对于 Wnt/β-连环蛋白信号转导是不可或缺的，从而解释了为什么 (P)RR 缺失（与肾素缺失不同）即使仅限于特定细胞，如心肌细胞、足细胞和平滑肌细胞，也是致命的。此外，最近的研究表明，(P)RR 可能在脂蛋白代谢和整体能量代谢中发挥重要作用。在这篇综述中，我们总结了 (P)RR 有争议的与 RAS 相关的作用，并批判性地回顾了 (P)RR 的新的非 RAS 相关功能，最后讨论了靶向 (P)RR 治疗心血管疾病的潜力。
