WDR72 Is Required for Urinary Acidification and Normal H + ‐ ATPase Activity in Intercalated Cells in Mice

ABSTRACT Aim Biallelic inactivating WDR72 variants are linked to distal renal tubular acidosis (dRTA), nephrocalcinosis, and amelogenesis imperfecta. The kidney shows high WDR72 expression; its precise localization and function remain unclear. WDR72 is a member of the WD40 repeat domain protein family—a large group of scaffold proteins involved in various pathways, including vesicular trafficking—which has been suggested as a potential role for WDR72. This study investigates WDR72 expression and its role in renal acid–base homeostasis. Methods We analyzed WDR72/Wdr72 expression in single‐cell transcriptome data from human and murine kidneys. We characterized Wdr72 −/− female and male mice and assessed Wdr72 mRNA and protein localization, the ability of the kidney to excrete acid, and the expression and function of the H + ‐ATPase. Results Transcriptome data showed that WDR72/Wdr72 is highly expressed in intercalated cells and other nephron segments. Immunohistochemistry localized WDR72 mostly at the apical membrane of type A‐intercalated cells (A‐IC). Wdr72 −/− mice exhibited alkaline urine under normal conditions, but only female knockout mice developed a pronounced metabolic acidosis upon dietary acid loading. Western blot analyses revealed sex‐dependent WDR72 expression changes with acid loading. Expression of several H + ‐ATPase subunits was dysregulated in Wdr72 −/− kidneys while their localization in intercalated cells remained intact. Lower expression of H + ‐ATPase subunits was paralleled by reduced H + ‐ATPase activity observed in isolated microperfused collecting ducts. Conclusion These findings identify WDR72 as a critical regulator of type A‐intercalated cell dependent urinary acidification, modulating H + ‐ATPase activity. The sex‐specific metabolic phenotype reveals a novel mechanism underlying sex differences in renal acid handling.