MicroRNA in extracellular vesicles released by damaged podocytes promote apoptosis of renal tubular epithelial cells

Abstract

Tubular injury and fibrosis are associated with progressive kidney dysfunction in advanced glomerular disease. Glomerulotubular crosstalk is thought to contribute to tubular injury. microRNAs (miRNAs) in extracellular vesicles (EVs) can modulate distant cells. We hypothesized that miRNAs in EVs derived from injured podocytes lead to tubular epithelial cell damage. As proof of this concept, tubular epithelial (HK2) cells were cultured with exosomes from puromycin-treated or healthy human podocytes, and damage was assessed. Sequencing analysis revealed the miRNA repertoire of podocyte EVs. RNA sequencing identified 63 upregulated miRNAs in EVs from puromycin-treated podocytes. Among them, five miRNAs (miR-149, -424, -542, -582, and -874) were selected as candidates for inducing tubular apoptosis according to a literature-based search. To validate the effect of the miRNAs, HK2 cells were treated with miRNA mimics. EVs from injured podocytes induced apoptosis and p38 phosphorylation of HK2 cells. The miRNA-424 and 149 mimics led to apoptosis of HK2 cells. These results show that miRNAs in EVs from injured podocytes lead to damage to tubular epithelial cells, which may contribute to the development of tubular injury in glomerular disease.