# CLDN5 as a novel modulator of podocyte adhesion to extracellular matrix via β1-integrin binding

## TL;DR

This study shows that CLDN5 helps kidney cells stick to their surroundings by working with β1-integrin, which is important for kidney health and disease prevention.

## Contribution

The study identifies CLDN5 as a novel modulator of podocyte adhesion via β1-integrin binding.

## Key findings

- CLDN5 localizes at the podocyte-GBM interface and colocalizes with β1-integrin.
- CLDN5 deletion impairs podocyte adhesion and resistance to mechanical stress.
- CLDN5 stabilizes β1-integrin by inhibiting its ubiquitination and degradation.

## Abstract

The intricate glomerular filtration barrier relies on robust podocyte adhesion to the glomerular basement membrane (GBM), a process critical for kidney function and often compromised in chronic kidney diseases. Here, we reveal that the four-transmembrane protein CLDN5 is an important molecule regulating podocyte adhesion. Utilizing super-resolution imaging, we pinpoint CLDN5’s localization at the podocyte-GBM interface, where it notably colocalizes with β1-integrin. CLDN5 deletion in podocytes profoundly impairs cell adhesion, spreading, and resistance to mechanical stress in vitro. Mechanistically, CLDN5 forms a stable complex with β1-integrin, and its loss leads to a significant reduction in β1-integrin protein levels coupled with aberrant localization. CLDN5 binds to the intracellular domain of β1-integrin via its intracellular loop and C-terminal domains, thereby impeding HUWE1-mediated ubiquitination at lysine K774 and subsequent proteasomal degradation as well as ensuring proper membrane localization of β1-integrin. The protective role of CLDN5 in maintaining podocyte integrity is supported by in vivo studies, demonstrating markedly exacerbated renal injury in Cldn5-KO mice subjected to hypertensive and adriamycin-induced injury models. These findings not only broaden our understanding of the extra-junctional roles of claudin proteins but also provide critical molecular insights into the complex mechanisms by which podocytes maintain integrity and withstand mechanical forces within the glomerulus.