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International Journal of Pharmacology
Mutation of ATP6V0A4 Gene Leads to Acid-base Disturbance and Inferred in Kidney Stone Formation
Lizhong Han, Mingming Li , Hao Wang, Guanjun Lu and Peijun Li

Background and Objective: The mutation in the V-type proton ATPase enzyme is encoded by the ATP6V0A4 gene and it leads to renal tubular acidosis associated with preserved hearing. Both in mice and human, the B1 and A4 subunit are the two important subunits which play a major role. The mutation of B1 subunit of heterozygous carriers in human leads to incomplete dRTA and calcium deposits (kidney stone) in humans. Therefore, the present study aimed to investigate the development of acid-base disturbances in ATP6V0A4 gene mutation in mice during a seven-day acid-load. Materials and Methods: In this investigation ATP6V0A4+/+ (wildtype), ATP6V0A4+/- (heterozygous) and ATP6V0A4-/- (homozygous) mice were subjected to 7 days acid-load and the metabolic and biochemical changes were monitored and analyzed to observe the acid-base balance, kidney function and protein expression. Results: The study observed that ATP6V0A4-/- mice tend to have a high level of alkali urine and low concentration of NH4 level. On the other hand, the ATP6V0A4+/- mice observed no significant difference in the biochemical parameters for urine analysis. But the heterozygous (+/-) mice observed a higher level of Cl and pCO2. The study observed that ATP6V0A4+/+ and ATP6V0A4+/- mice had localized intercalated cells in the B1 subunit. However, the expression of B1 and A4 subunit gradually decreased in the ATP6V0A4+/+ renal membrane. There were the reduction in the B1 subunit in the ATP6V0A4-/- and the ablation of B1 subunit was observed in the collecting duct of the ATP6V0A4-/- mice. Conclusion: To conclude, the study observed that ATP6V0A4+/- mice developed a mild distal-RTA which is compensated by respiration and in the absence of the B1 subunit for the compensatory mechanism occurs inside the collecting duct of ATP6V0A4-/- mice kidneys.
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