# Mutations in UMOD Contribute to the Pathogenesis of ADTKD‐UMOD by Influencing the Function of Complement Factor H

## TL;DR

Mutations in the UMOD gene reduce its ability to regulate the complement system, contributing to kidney disease by causing excessive inflammation and tissue damage.

## Contribution

This study reveals how UMOD mutations impair complement factor H function, linking this mechanism to the progression of ADTKD-UMOD.

## Key findings

- Patient-derived uromodulin mutants show reduced binding to complement factor H and impaired C3b cleavage.
- Wild-type uromodulin significantly enhances C3b degradation and inhibits hemolysis, unlike mutant forms.
- Impaired UMOD-cFH interactions may lead to unchecked complement activation and tubulointerstitial fibrosis.

## Abstract

Tubular atrophy and interstitial fibrosis are basic renal pathological changes in autosomal dominant tubulointerstitial kidney disease (ADTKD). Reduced secretion or abnormal structure of uromodulin (UMOD) are recognised pathogenic factors of ADTKD. Studies show uromodulin binds complement factor H (cFH), enhancing its ability to inhibit complement activation. Overactivation of the complement system contributes to tubulointerstitial injury. Therefore, exploring the UMOD–tubulointerstitial fibrosis link may aid in the development of treatment for ADTKD‐UMOD. Immunofluorescence staining detected complement deposition in patients' kidneys. Uromodulin's binding affinity for cFH was assessed using microthermophoresis. The effect of this binding on cFH function was analysed using C3b degradation and erythrocyte hemolysis tests. Recombinant wild‐type and mutant uromodulin proteins were expressed and tested using the aforementioned methods. Complement factor B was detected in the kidneys of patients with ADTKD‐UMOD. Patient‐derived uromodulin showed reduced binding to cFH and decreased capacity to assist in C3b cleavage and hemolysis inhibition. Recombinant wild‐type uromodulin significantly enhanced C3b cleavage (p < 0.001) and inhibited hemolysis (p < 0.01). Uromodulin mutants showed reduced binding to cFH and limited ability to promote C3b degradation, with no significant hemolysis inhibition. Impaired interactions between mutants and cFH may lead to insufficient inhibition of complement activity, triggering tubulointerstitial fibrosis.