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.