WDR72 Is Required for Urinary Acidification and Normal H(+)-ATPase 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.