Adaptation by the collecting duct to an exogenous acid load is blunted by deletion of the proton-sensing receptor GPR4

Am J Physiol Renal Physiol. 2015 Jul 15;309(2):F120-36. doi: 10.1152/ajprenal.00507.2014. Epub 2015 May 13.

Abstract

We previously reported that the deletion of the pH sensor GPR4 causes a non-gap metabolic acidosis and defective net acid excretion (NAE) in the GPR4 knockout mouse (GPR4-/-) (Sun X, Yang LV, Tiegs BC, Arend LJ, McGraw DW, Penn RB, and Petrovic S. J Am Soc Nephrol 21: 1745-1755, 2010). Since the major regulatory site of NAE in the kidney is the collecting duct (CD), we examined acid-base transport proteins in intercalated cells (ICs) of the CD and found comparable mRNA expression of kidney anion exchanger 1 (kAE1), pendrin, and the a4 subunit of H(+)-ATPase in GPR4-/- vs. +/+. However, NH4Cl loading elicited adaptive doubling of AE1 mRNA in GPR4+/+, but a 50% less pronounced response in GPR4-/-. In GPR4+/+, NH4Cl loading evoked a cellular response characterized by an increase in AE1-labeled and a decrease in pendrin-labeled ICs similar to what was reported in rabbits and rats. This response did not occur in GPR4-/-. Microperfusion experiments demonstrated that the activity of the basolateral Cl(-)/HCO3(-) exchanger, kAE1, in CDs isolated from GPR4-/- failed to increase with NH4Cl loading, in contrast to the increase observed in GPR4+/+. Therefore, the deficiency of GPR4 blunted, but did not eliminate the adaptive response to an acid load, suggesting a compensatory response from other pH/CO2/bicarbonate sensors. Indeed, the expression of the calcium-sensing receptor (CaSR) was nearly doubled in GPR4-/- kidneys, in the absence of apparent disturbances of Ca(2+) homeostasis. In summary, the expression and activity of the key transport proteins in GPR4-/- mice are consistent with spontaneous metabolic acidosis, but the adaptive response to a superimposed exogenous acid load is blunted and might be partially compensated for by CaSR.

Keywords: CasR; GPR4 knockouts; acid sensor; collecting duct; metabolic acidosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid-Base Equilibrium*
  • Acidosis, Renal Tubular / metabolism
  • Adaptation, Physiological
  • Animals
  • Anion Exchange Protein 1, Erythrocyte / metabolism*
  • Anion Transport Proteins / metabolism
  • Kidney Tubules, Collecting / metabolism*
  • Mice, Knockout
  • Receptors, Calcium-Sensing / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / metabolism
  • Sulfate Transporters

Substances

  • Anion Exchange Protein 1, Erythrocyte
  • Anion Transport Proteins
  • GPR4 protein, mouse
  • Receptors, Calcium-Sensing
  • Receptors, G-Protein-Coupled
  • Slc26a4 protein, mouse
  • Slc4a1 protein, mouse
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Sulfate Transporters