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

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.