Vacuolar proton pump a4 subunit is critical for inner ear development and renal function

Abstract

Renal distal tubular acidosis (dRTA) has been associated with human ATP6V0A4 (a4 subunit of the proton pump) gene mutations. This disease is characterised by acidic blood pH, low blood bicarbonate and potassium concentrations, and often, hypercalciuria leading to nephrocalcinosis. Some patients with ATP6V0A4 mutations also develop late onset senso‐neurinal deafness.We generated a mouse model deficient for the a4 subunit. Survival rate of KO mice was dramatically reduced and did not exceed 7–8 weeks of age. Mouse deficient for the Atp6v0a4 gene (a4−/−) recapitulated most of the renal impairment seen in patients with dRTA since they exhibited life‐threatening metabolic acidosis consecutive to a marked reduction in renal acidification capacity. This was associated with complete hearing loss associated with a strong enlargment of the endolymphatic sac of the inner ear. In the kidney, a4 subunit has been localised in the proximal tubule and in the intercalated cells of the collecting duct which are two renal segments involved in acid‐base balance. Histo‐morphological analysis of a4−/− mouse kidneys revealed a profound lysosomal remodelling in the proximal tubule associated with an abnormal trafficking of the proton pump in both proximal tubule and intercalated cells. Their low molecular weight proteinuria was explained by a general proximal tubule dysfunction. We conclude that A4 subunit is a mandatory component for the assembly of the vacuolar proton pump ATPase complex and is critical for inner development, distal acidification and proximal tubule absorptive capacity.