(Pro)Renin Receptor Mediates Antidiuretic Action of Vasopressin/Prostaglandin EP4 Subtype

Abstract

Within the kidney, (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), particularly in intercalated cells and is regulated by the EP4 subtype. Here we investigated the function of CD PRR during antidiuresis and defined its relationship with the EP4 subtype as well as vasopressin (VP). Water deprivation (WD) elevated renal PRR expression and urinary soluble PRR (sPRR) excretion in rats. Intrarenal infusion of a PRR decoy peptide PRO20 to rats partially attenuated the decrease in urine volume and the increase in urine osmolality in response to 48‐h WD, in parallel with suppressed aquaporin‐2 expression; a similar effect was seen with EP4 antagonism. The mice lacking PRR in the CD exhibited increased urine volume and decreased urine osmolality at basal condition and exhibited impaired urine concentrating capability after WD, accompanied with severe volume loss and a dangerous level of plasma hyperosmolality. In primary culture of rat inner medullary collecting duct (IMCD) cells, exposure to 10 nM prorenin for 24 h remarkably induced AQP2 protein expression, which was blunted by a PRR decoy inhibitor PRO20 and PRR siRNA. VP treatment for 24 h similarly induced aquaporin‐2 (AQP2) expression, accompanied with increased release of PGE2 and sPRR; the AQP2 upregulation was blunted by antagonism of EP4 or PRR. Overall, we have defined a VP/PGE2/EP4/PRR/AQP2 pathway that appears to play an important role in regulation of urine concentrating capability.Support or Funding InformationThis work was supported by National Institutes of Health Grants DK104072 and DK094956, VA Merit Review from the Department of Veterans Affairs, and National Natural Science Foundation of China Grant No. 91439205 and No. 31330037. T. Yang is a Research Career Scientist in the Department of Veterans Affairs.