Antidiuretic Action of Collecting Duct (Pro)Renin Receptor Downstream of Vasopressin and PGE2 Receptor EP4

Abstract

Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), particularly in intercalated cells, and it is regulated by the PGE receptor EP Notably, EP also controls urinary concentration through regulation of aquaporin 2 (AQP2). Here, we tested the hypothesis that sequential activation of EP and PRR determines AQP2 expression in the CD, thus mediating the antidiuretic action of vasopressin (AVP). Water deprivation (WD) elevated renal PRR expression and urinary soluble PRR excretion in rats. Intrarenal infusion of a PRR decoy peptide, PRO20, or an EP antagonist partially prevented the decrease in urine volume and the increase in urine osmolality and AQP2 expression induced by 48-hour WD. In primary cultures of rat inner medullary CD cells, AQP2 expression induced by AVP treatment for 24 hours depended on sequential activation of the EP receptor and PRR. Additionally, mice lacking PRR in the CD exhibited increased urine volume and decreased urine osmolality under basal conditions and impaired urine concentrating capability accompanied by severe volume loss and a dangerous level of plasma hyperosmolality after WD. Together, these results suggest a previously undescribed linear AVP/PGE/EP/PRR pathway in the CD for regulation of AQP2 expression and urine concentrating capability.

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

“…This result also suggests that the production of renal sPRR may be under the direct control of the AVP-V2R pathway. In support of this notion, we have shown that exposure of the CD cells to AVP stimulates the release of sPRR (14). Fig.…”

“…To our knowledge, no prior studies have reported a biological function of sPRR. We recently used pharmacological and conditional gene-knockout approaches to demonstrate that CD PRR has an essential role in determining renal AQP2 expression and urine-concentrating capability (14). In the present study, we discovered that sPRR acts via FZD8-dependent activation of β-catenin signaling that leads to increased AQP2 expression and thus enhanced urineconcentrating capability.…”

“…However, serum sPRR was not correlated with serum renin, prorenin, or aldosterone in healthy subjects or in patients with diabetes and hypertension (12). To our knowledge no prior studies have reported a biological function of sPRR in any condition.Within the kidney, PRR is expressed abundantly in the distal nephron, particularly in intercalated cells of the collecting duct (CD) (13,14). A functional role of PRR in regulating renal aquaporin 2 (AQP2) expression and urine-concentrating capability has been revealed by analysis of mice with conditional deletion of PRR in the nephron (15) and the CD (14).…”

“…Within the kidney, PRR is expressed abundantly in the distal nephron, particularly in intercalated cells of the collecting duct (CD) (13,14). A functional role of PRR in regulating renal aquaporin 2 (AQP2) expression and urine-concentrating capability has been revealed by analysis of mice with conditional deletion of PRR in the nephron (15) and the CD (14).…”

“…A functional role of PRR in regulating renal aquaporin 2 (AQP2) expression and urine-concentrating capability has been revealed by analysis of mice with conditional deletion of PRR in the nephron (15) and the CD (14). However, whether the antidiuretic action of CD PRR is conferred by sPRR remains elusive.…”