Deletion of the pH Sensor GPR4 Decreases Renal Acid Excretion is a study published bu Sun, et al in the October  2010 Journal of the American Society of Nephrology. “Proton receptors are G protein-coupled receptors that accept protons as ligands and function as pH sensors. One of the proton receptors, GPR4, is relatively abundant in the kidney, but its potential role in acid-base homeostasis is unknown.” [Quotation from the above paper]

Sun and colleagues observed GPR4 expression in the kidney cortex, in the outer and inner medulla, in isolated kidney collecting ducts, and in cultured outer and inner medullary collecting duct cells. The most interesting part of this study was the measurement of acid-base status in GPR4 knockout mice – ie, mice that have been genetically changed so they cannot express the receptor but which are otherwise identical to control animals. If this receptor is important in acid-base regulation then mice which lack it should have a defect in urinary acidification.

The knockout mice had lower pCO2 (35.7 vs 39.6 mm Hg) than their wild counterparts. Similarly HCO3 was lower (20.3 vs 24.0 meq/l). But the symmetrical decline in both resulted in pH values that were not significantly different ( 7.37 vs 7.39). Net acid excretion was lower in the knockout animals than in the controls. The investigators interpret these finding to indicate a mild compensated metabolic acidosis resulting from a modest impairment of urinary acidification in the mice that lacked GPR4.

This interpretation is almost certainly correct, but if you want to nitpick, and nitpicking is the essence of science, mild compensated respiratory alkalosis could give the exact same findings.  Of course, there’s no reason why the loss of a proton receptor should cause respiratory alkalosis. But the only way to completely exclude it would be to have balance studies over time which showed that the fall in HCO3 preceded the fall in pCO2. This is a study not worth anyone’s time, however.

These mice were also acid loaded. This resulted in lower net acid and ammonium excretion in the knockout mice than in the wild type. But all other blood and urine acid-base parameters were the same. The authors don’t dwell on this interesting finding other than to say the loss of the proton receptor impaired urinary acidification. If urinary excretion was decreased in the knockouts but blood acid-base status was no different from control then extra-renal buffering must have been enhanced in the animals that lacked GPR4. The current study casts no light on why this should happen. Nonetheless, the conclusion that the proton receptor plays an important role in the sensing mechanism that integrates the kidney’s response to changes in pH, pCO2, and HCO3 seems valid. Given the small changes that result from its absence this receptor seems to play a small role in overall urinary acidification.