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Adhesion‐GPCR Gpr116 (ADGRF5) is a Regulator of Urine Acidification
Author(s) -
Zaidman Nathan,
Tomilin Viktor,
Damarla Mahendra,
Tidmore Josephine,
Pochynyuk Oleh,
Pluznick Jennifer
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01986
Subject(s) - g protein coupled receptor , kidney , receptor , hek 293 cells , urine , extracellular , chemistry , knockout mouse , medicine , microbiology and biotechnology , biology , endocrinology , biochemistry
G‐protein coupled receptors (GPCR) are a large and diverse family of integral membrane proteins that recognize a tremendous assortment of extracellular molecules including neurotransmitters, hormones, light and odors. They are a common target of pharmaceutical drug development, and uncovering the function of novel GPCRs in the kidney represents a wealth of untapped therapeutic potential. We previously performed an mRNA screen for novel GPCRs in the kidney to identify promising yet overlooked renal GPCRs. This screen revealed that Gpr116, an adhesion‐class GPCR, is highly expressed in the kidney. To understand the role of Gpr116 in renal physiology, we have taken a multidisciplinary approach. Using transfected HEK293 cells expressing cloned Gpr116, we have validated a monoclonal antibody for Gpr116. In murine kidney, this antibody indicates localization of Gpr116 to intercalated cells (ICs) in the collecting duct of mouse kidneys. This staining is absent in kidneys from targeted knockout (KO) of Gpr116 in renal tubules (Gpr116flox/flox, ksp‐Cre). Additionally, kidney‐specific KO animals have significantly (p<0.02) reduced urine pH (5.66±0.29, n=9) compared to wild‐type (WT; 5.96±0.23, n=15) littermates. Challenging the animals with an acid load (280mM NH 4 Cl added to drinking water) significantly acidifies WT urine (5.71±0.18, n=14, p<0.03) but does not significantly reduce KO urine pH (5.55±0.20, n=9), suggesting the loss of Gpr116 from α‐ICs is sufficient to maximally acidify urine. KO mice do not have significantly more ICs compared to WT. Interestingly, the loss of acid in the urine is accompanied by a small, but significant (p=0.001), increase in blood pH, and a small, but significant (p<0.05), decrease in pCO 2 compared to WT. 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 HCO 3 − by α‐ICs. This study establishes a physiologic role of the previously understudied Gpr116 in the murine kidney and demonstrates the scientific potential of future investigations into novel GPCRs. Support or Funding Information Research was funded by NIH F32DK116499 (N.A.Z.) and NIH R01DK107726 (J.L.P.).