Acta physiologica (Oxford, England) · 2026
WDR72 Is Required for Urinary Acidification and Normal H+-ATPase Activity in Intercalated Cells in Mice.
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Auwerx Hannah, Busch-Dohr Moana, Li Xiaoxu, Wagner Carsten A, Bourgeois Soline
Аннотация
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.
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.