Podocyte-Derived Extracellular Vesicles Induce Endothelial Dysfunction by Triggering ER Stress in Glomerular Disease.

Abstract

Podocyte injury and endothelial cell dysfunction are the hallmarks of glomerular disease. How these two events are connected remains largely unknown. This study aimed to delineate the role of extracellular vesicles (EVs) in mediating podocyte-endothelial communication in glomerular disease. Podocyte-derived EVs were characterized by nanoparticle tracking analysis and electron microscopy. Proteomic analyses were used to characterize proteins in the EVs. The involvement of integrin αvβ1, focal adhesion kinase (FAK), endoplasmic reticulum (ER) stress-related proteins was investigated using siRNA inhibition, neutralizing antibodies, small molecule inhibitors in vitro and in vivo. We found that podocyte injury was associated with an increased secretion of EVs, in which integrin αvβ1 was upregulated and enriched. Podocyte-derived EVs were recruited by endothelium via secreting fibronectin. Integrin αvβ1 from podocyte EVs was then transferred to endothelial cells, in which it activated the FAK and triggered ER stress, ultimately leading to endothelial cell apoptosis. In mouse models of glomerular disease, intravenous injection of the EVs from injured podocytes exacerbated endothelial ER stress and apoptosis, while inhibition of integrin β1 signaling blocked this effect. Similarly, inhibition of EV secretion by dimethyl amiloride preserved endothelial integrity and ameliorated glomerulosclerosis in vivo. These studies indicate that podocyte injury causes endothelial dysfunction by releasing integrin αvβ1-enriched EVs, which trigger FAK-mediated ER stress and apoptosis. Therefore, targeted blockade of EV secretion or integrin αvβ1 signaling may hold promise for protecting against endothelial dysfunction in glomerular disease.