Haploinsufficiency of the Mouse Atp6v1b1 Gene Leads to a Mild Acid-Base Disturbance with Implications for Kidney Stone Disease

Abstract

Background/Aims: Homozygous mutations or deletion of the ATP6V1B1 gene encoding for the B1 subunit of the vacuolar H⁺-ATPase leads to distal renal tubular acidosis in man and mice. In humans, heterozygous carriers of B1 mutations can develop incomplete dRTA with nephroclacinosis. Here, we investigated whether Atp6v1b1^+/- mice also develop acid-base disturbances during an HCl acid load. Methods: We subjected Atp6v1b1^+/+, Atp6v1b1^+/-, Atp6v1b1^-/- to an HCl-load for 7 days and investigated acid-base status, kidney function, and expression of renal acid-base transport proteins. Results: Atp6v1b1^-/- mice had more alkaline urine and low ammoniuria, whereas Atp6v1b1^+/- mice showed no difference in their urine parameters but higher blood chloride and lower blood pCO₂ compared to controls. Subcellular localization of a4 and B2 subunits of H⁺-ATPase were unchanged within the 3 genotypes and Atp6v1b1^+/+ and Atp6v1b1^+/- mice exhibited a similar luminal localization of B1 subunit in intercalated cells. However, B1, B2 and a4 expression were decreased in renal membrane fractions from Atp6v1b1^+/- mice compared to Atp6v1b1^+/+ while B2 and a4 were unchanged and B1 protein was reduced in Atp6v1b+^-/- kidneys. Compensatory mechanisms of B1 ablation were found only in the collecting duct with a down-regulation of pendrin in Atp6v1b1^-/- mice. Conclusions: In conclusion, 1) Atp6v1b1^+/- mice developed a mild incomplete dRTA. dRTA is partly compensated by respiration. 2) Compensatory mechanisms for the absence of B1 take place only in the collecting duct of Atp6v1b1^-/- kidneys.