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

## TL;DR

This study shows that the WDR72 protein is essential for kidney cells to properly acidify urine, and its absence leads to acid balance issues, especially in female mice.

## Contribution

The study identifies WDR72 as a key regulator of H+‐ATPase activity in kidney intercalated cells and reveals a sex-specific role in acid-base homeostasis.

## Key findings

- WDR72 is highly expressed in intercalated cells and localized at the apical membrane of type A-intercalated cells.
- Wdr72−/− mice show impaired urinary acidification and reduced H+‐ATPase activity, with sex-specific differences in acid handling.
- Loss of WDR72 leads to dysregulated H+‐ATPase subunit expression without affecting their localization.

## Abstract

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.

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.

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.

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.