(Pro)renin receptor (PRR) binds prorenin/renin in vitro to increase their catalytic activity and therefore is postulated to be a regulator of renin. Soluble PRR (sPRR) residing in the extracellular domain of PRR is produced by furin or ADAM19-dependent cleavage process and has been widely studied as a disease biomarker. Although PRR has an established role in embryogenesis in both low vertebrates and mammals, the potential role of PRR/sPRR in regulation of mammalian renal function and blood pressure largely remains elusive. Within the kidney, PRR is predominately expressed in the distal nephron, particularly the intercalated cells of the collecting duct (CD). In preliminary studies, we discovered a previously undescribed paracrine action of PRR/sPRR with intercalated cell-derived sPRR acting on principal cells to stimulate ENaC-mediated Na+ reabsorption. We presented further evidence that PRR/sPRR- mediated paracrine control of Na+ transport contributes to pathogenesis of mineralocorticoid-salt hypertension. This proposal will test the overall hypothesis that during mineralocorticoid excess, the expression of PRR/sPRR is increased in the distal nephron where sPRR binds Frizzled-8 to activate ?-catenin signaling that activates adenylyl cyclase-3 (AC3)/cAMP/PKA pathway that stimulates ENaC transcription and activity and hence hypertension and kidney injury. To test this hypothesis, we will employ conditional gene targeting techniques to evaluate the contribution of CD PRR and ?-catenin to ENaC activation and hypertension. Moreover, we will dissect sPRR- induced signaling mechanisms involving coordinated activation of Frizzled-8/?-catenin and AC3/cAMP/PKA pathways in the CD cells. Lastly, we will explore a novel therapeutic potential of inhibitors of ?-catenin signaling in mineralocorticoid-salt hypertension. Overall, this proposal is expected to offer novel insight into the function of renal PRR/sPRR in hypertension and kidney injury.
Nearly one third of the adults in the United States are suffering from hypertension and only half of them can attain the optimal blood pressure control. The current proposal has the potential to advance our understanding of the fundamental mechanism of hypertension and also to identify a novel target for antihypertensive therapies.
