(Pro)renin Receptor and Oxidative Stress Friend or Foe?

The renin-angiotensin-aldosterone system (RAAS) plays pivotal role in the pathogenesis of hypertension and renal disease. Oxidative stress is one of the important mechanisms of renal diseases induced by activated RAAS. Recently (Pro)renin receptor (PRR) has been identified, and its importance in the initiation and progression of renal diseases is attracting attentions. Although PRR causes renal injury by increased oxidative stress through Ang II-dependent and independent mechanism, genetic defect in PRR is reported to causes abnormal phenotypes. Recently, PRR has been reported to activate vacuolar H+- ATPase (V-ATPase), that is essential for survive of cells as proton transporter, contributing to keeping cellular pH homeostasis. Loss of V-ATPase activity has been also reported to result in increased oxidative stress. Thus activating PRR may suppress oxidating stress through V-ATPase activation. Actually, loss of this V-ATPase activity has been reported to result in defects in CNS, renal tubular acidosis, osteoporosis, and others. We would also like to show the evolutional relationship between ATP synthase of mitochondria and V-ATPase. ATP synthase of mitochondria resembles V-ATPase in construction but direction of proton flow is opposite. And only V-ATPase has ATP6ap2 as associate protein from PRR and anti-oxidative property. This strange resemblance in structure and opposite anti-oxidative capacity and proton flow across cell membrane reminds us the possibility that mitochondria originally had V-ATPase in cell membrane, but lost ATP6ap2 and proton flow reversed, resulting in loss of antioxidative capacity and gaining of ATP producing capacity in the process of symbiosis and retrogression of mitochondrial DNA.