title: Adaptation by the collecting duct to an exogenous acid load is blunted by deletion of the proton-sensing receptor GPR4.
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.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Xuming
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stephens
authors.affiliation: Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina;
authors.forename: Thomas D
authors.initials: TD
authors.lastname: DuBose
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina; Claude D. Pepper Older Americans Independence Center, Wake Forest School of Medicine, Winston-Salem, North Carolina; Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston-Salem, North Carolina; and snpetrov@wakehealth.edu.
authors.forename: Snezana
authors.initials: S
authors.lastname: Petrovic
mesh_terms: D000136:Acid-Base Equilibrium; D000141:Acidosis, Renal Tubular / Q000378:metabolism; D000222:Adaptation, Physiological; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism*; D027321:Anion Transport Proteins / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D018345:Mice, Knockout; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D000076988:Sulfate Transporters
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D027321:Anion Transport Proteins; C517811:GPR4 protein, mouse; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; C494849:Slc26a4 protein, mouse; C523515:Slc4a1 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000076988:Sulfate Transporters
keywords: CasR; GPR4 knockouts; acid sensor; collecting duct; metabolic acidosis