Soluble (pro)renin receptor as a novel regulator of renal medullary Na⁺ reabsorption

Epithelial sodium channel (ENaC) represents a major route of Na + reabsorption in the aldosterone-sensitive distal nephron where the bulk of ENaC activity is considered to occur in the cortical collecting duct (CCD). Relatively, ENaC activity in the medulla, especially the inner medulla, is often neglected. (Pro)renin receptor (PRR), also termed ATP6ap2, a newly characterized member of the renin-angiotensin system, has emerged as an important regulator of ENaC in the distal nephron. The ENaC regulatory action of PRR is largely mediated by the 28 kDa soluble PRR (sPRR). Although all three subunits of ENaC are under the control of aldosterone, sPRR only mediates the upregulation of α-ENaC but not the other two subunits. Furthermore, sPRR-dependent regulation of α-ENaC only occurs in the renal inner medulla but not in the cortex. sPRR also rapidly upregulates ENaC activity via Nox4-derived H 2 O 2 . Overall, sPRR has emerged as an important regulator of renal medullary Na + reabsorption in the context of overactivation of the renin-angiotensin-aldosterone system.