Kidney-specific Wdr72 deletion leads to incomplete distal renal tubular acidosis through impaired V-ATPase B1 subunit localization

Abstract

BackgroundDistal renal tubular acidosis (dRTA) is a rare kidney disorder characterized by impaired urinary acidification due to defective proton secretion in type A intercalated cells of the collecting duct. Recently, pathogenic variants in the human gene encoding the WD Repeat Domain 72 protein (WDR72) have been reported in patients with dRTA, yet the physiological role of WDR72 in the kidney remains unknown. MethodsTo elucidate the renal function of Wdr72, we generated a kidney-specific knockout mouse model (Wdr72fl/fl;Pax8-Cre+) and assessed acid-base homeostasis under baseline, acute, and chronic acid loading. ResultsWdr72fl/fl;Pax8-Cre+ mice displayed persistently elevated urinary pH, reduced titratable acid and net acid excretion under basal and acid-loaded conditions, consistent with incomplete dRTA. While the systemic pH remained unchanged compared to controls under standard diet, chronic acid load led to mild hyperchloremic, hypokalemic metabolic acidosis. Notably, urinary NH excretion was increased upon acid loading accompanied by upregulation of key ammoniagenesis enzymes, which was detected even under basal conditions, consistent with a compensatory activation of proximal tubular acid excretion pathways. The total and membranous abundance of the V-ATPase B1 subunit decreased markedly within the kidney, despite unchanged transcript levels, suggesting a defect in V-ATPase trafficking or assembly. In addition, morphometric analyses revealed an increased proportion of type A intercalating cells that failed to expand upon acid loading, indicating defective adaptive plasticity. ConclusionsKidney-specific Wdr72 deletion impairs distal urinary acidification through reduced V-ATPase abundance and membranous targeting, altered intercalated cell morphology, and limited adaptive remodeling, resulting in incomplete dRTA. Upregulation of renal ammoniagenesis partially compensates the acidification defect. These findings highlight WDR72 as a key regulator of distal nephron acid-base homeostasis and offer mechanistic insight into WDR72-associated dRTA. Key PointsO_LIKidney-specific deletion of Wdr72 reduced Atp6v1b1 membranous localization in intercalated cells. C_LIO_LIKidney-specific Wdr72 knockout altered intercalated cell morphology, and limited their adaptive remodeling. C_LIO_LIThe lack of the renal Wdr72 resulted in incomplete dRTA, compensated partially by elevated ammoniagenesis. C_LI