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

• DOI: 10.1172/jci.insight.124174
• Publication Date: 2019-04-03T17:41:59Z
• Authors: Fei Wang; Chuanming Xu; Renfei Luo; Kexin Peng; Nirupama Ramkumar; Shiying Xie; Xiaohan Lu; Long Zhao; Chang-Jiang Zuo; Donald E. Kohan; Tianxin Yang
• Keywords: Male; Mice, Knockout; Receptors, Vasopressin; 0303 health sciences; Aquaporin 2; Pyrrolidines; Primary Cell Culture; Epithelial Cells; Receptors, Cell Surface; Peptide Fragments; 6. Clean water; Rats; Kidney Concentrating Ability; Mice; Proton-Translocating ATPases; 03 medical and health sciences; Models, Animal; Renin; Animals; Proprotein Convertases; Kidney Tubules, Collecting; Antidiuretic Hormone Receptor Antagonists; Cells, Cultured

The antidiuretic hormone vasopressin (AVP), acting through its type 2 receptor (V2R) 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 V2R. In cultured inner medullary collecting duct (IMCD) cells, AVP-induced V2R 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 V2R 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 V2R and aquaporin-2 (AQP2). Together, these results support that S1P-derived sPRR exerts a key role in determining renal V2R expression and, thus, urine concentrating capability.