(Pro)renin receptor as a therapeutic target for the treatment of cardiovascular diseases?
The discovery of the (pro)renin receptor [(P)RR] 15 years 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.