Adhesion-GPCR Gpr116 (ADGRF5) expression inhibits renal acid secretion

Nathan A. Zaidman, Viktor N. Tomilin, Naghmeh Hassanzadeh Khayyat, Mahendra Damarla, Josephine Tidmore, Diane E. Capen, Dennis Brown, Oleh M. Pochynyuk, Jennifer L. Pluznick

Research output: Contribution to journalArticlepeer-review

Abstract

The diversity and near universal expression of G protein-coupled receptors (GPCR) reflects their involvement in most physiological processes. The GPCR superfamily is the largest in the human genome, and GPCRs are common pharmaceutical targets. Therefore, uncovering the function of understudied GPCRs provides a wealth of untapped therapeutic potential. We previously identified an adhesion-class GPCR, Gpr116, as one of the most abundant GPCRs in the kidney. Here, we show that Gpr116 is highly expressed in specialized acid-secreting A-intercalated cells (A-ICs) in the kidney using both imaging and functional studies, and we demonstrate in situ receptor activation using a synthetic agonist peptide unique to Gpr116. Kidney-specific knockout (KO) of Gpr116 caused a significant reduction in urine pH (i.e., acidification) accompanied by an increase in blood pH and a decrease in pCO2compared to WT littermates. Additionally, immunogold electron microscopy shows a greater accumulation of V-ATPase proton pumps at the apical surface of A-ICs in KO mice compared to controls. Furthermore, pretreatment of split-open collecting ducts with the synthetic agonist peptide significantly inhibits proton flux in ICs. These data suggest a tonic inhibitory role for Gpr116 in the regulation of V-ATPase trafficking and urinary acidification. Thus, the absence of Gpr116 results in a primary excretion of acid in KO mouse urine, leading to mild metabolic alkalosis ("renal tubular alkalosis"). In conclusion, we have uncovered a significant role for Gpr116 in kidney physiology, which may further inform studies in other organ systems that express this GPCR, such as the lung, testes, and small intestine.

Original languageEnglish (US)
Pages (from-to)26470-26481
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number42
DOIs
StatePublished - Oct 20 2020

Keywords

  • A-intercalated cell
  • ADGRF5
  • Gpr116
  • Kidney
  • V-ATPase

ASJC Scopus subject areas

  • General

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