Zaidman, Nathan A, Tomilin , Viktor, Damarla, Mahendra, Tidmore, Josephine, Capen , Diane, Brown, Dennis, Pochynyuk, Oleh and Pluznick, Jennifer L (2020) Adhesion-GPCR Gpr116 (ADGRF5) is a Regulator of Urine Acidification and Surface Expression of the Vacuolar-type H+-ATPase in Renal α-Intercalated Cells. Proceedings of the National Academy of Sciences of the United States of America PNAS..

Abstract

The G protein-coupled receptor (GPCR) superfamily is among the largest in the human genome. Their diversity and nearly universal expression underlie their significance in many physiologic processes. GPCRs are a common target of pharmaceutical drug development, and uncovering the function of understudied GPCRs in the kidney represents a wealth of untapped therapeutic potential. We previously identified Gpr116, an adhesion-class GPCR, as one of the most highly expressed GPCRs in the kidney. In the present study, we confirm the localization of Gpr116 to the luminal membrane of acid-secreting α-intercalated cells (αICs) in the nephron using both imaging and functional studies, where we demonstrate in situ receptor activation using an agonist peptide unique to Gpr116. Additionally, kidney-specific knockout (KO) of Gpr116 caused a significant reduction to urine pH. Notably, the loss of acid in the urine is accompanied by a small, but significant, increase in blood pH, and a small, but significant, decrease in pCO2 compared to wild-type littermates. Results from transmission electron micrographs show greater accumulation of V-ATPase proton pumps at the surface of αICs in KO mice, suggesting a possible role for Gpr116 in the regulation of V-ATPase trafficking. We conclude that loss of Gpr116 from the nephron causes a primary loss of acid in the urine which results in a mild metabolic alkalosis (“renal tubular alkalosis”) due to reabsorption of HCO3- by αICs. This study establishes a significant physiologic role of the previously understudied Gpr116 in the murine kidney and demonstrates the scientific potential of future investigations into novel GPCRs.

Item Type:	Article
Date Deposited:	24 Nov 2020 00:45
Last Modified:	24 Nov 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41977