Site-1 protease-derived soluble (pro)renin receptor targets vasopressin receptor 2 to enhance urine concentrating capability

The antidiuretic hormone vasopressin (AVP), acting through its type 2 receptor (V(2)R) in the collecting duct (CD), critically controls urine concentrating capability. Here, we report that site-1 protease–derived (S1P-derived) soluble (pro)renin receptor (sPRR) participates in regulation of fluid homeostasis via targeting V(2)R. In cultured inner medullary collecting duct (IMCD) cells, AVP-induced V(2)R expression was blunted by a PRR antagonist, PRO20; a PRR-neutralizing antibody; or a S1P inhibitor, PF-429242. In parallel, sPRR release was increased by AVP and reduced by PF-429242. Administration of histidine-tagged sPRR, sPRR-His, stimulated V(2)R expression and also reversed the inhibitory effect of PF-429242 on the expression induced by AVP. PF-429242 treatment in C57/BL6 mice impaired urine concentrating capability, which was rescued by sPRR-His. This observation was recapitulated in mice with renal tubule–specific deletion of S1P. During the pharmacological or genetic manipulation of S1P alone or in combination with sPRR-His, the changes in urine concentration were paralleled with renal expression of V(2)R and aquaporin-2 (AQP2). Together, these results support that S1P-derived sPRR exerts a key role in determining renal V(2)R expression and, thus, urine concentrating capability.