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

  • JCI Insight. 2019 Apr 4;4(7):e124174. doi: 10.1172/jci.insight.124174.
Fei Wang  1  2 ,  Chuanming Xu  1  2 ,  Renfei Luo  1  2 ,  Kexin Peng  1  2 ,  Nirupama Ramkumar  1 ,  Shiying Xie  1  2 ,  Xiaohan Lu  1  2 ,  Long Zhao  1 ,  Chang-Jiang Zuo  1 ,  Donald E Kohan  1 ,  Tianxin Yang  1  2  3
Affiliations
  • 1. Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
  • 2. Institute of Hypertension, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 3. Institute of Hypertension and Renal Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
PMID: 30944256 DOI: 10.1172/jci.insight.124174
Abstract

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.

Keywords
Nephrology; Transport.
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