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.
Highlights
Glomerular podocytes are terminally differentiated cells and form the filtration barrier between endothelial cells and the basement membrane [1]
Podocyte extracellular vesicles (EVs) were characterized by nanoparticle tracking analysis
We found that EVs from injured podocytes induced tubular epithelial cell damage to the pathway that was activated in these cells
Summary
Glomerular podocytes are terminally differentiated cells and form the filtration barrier between endothelial cells and the basement membrane [1]. Stress conditions, such as high glucose, lead to podocyte injury, which is the first step in diabetic kidney disease, minimal change disease (MCD), and focal segmental glomerular sclerosis (FSGS) [2]. Glomerular injury leads to tubulointerstitial inflammation and fibrosis, which. The mechanism of tubulointerstitial injury in glomerular disease remains unclear. Extracellular vesicles (EVs) refer to all membrane-bound vesicles released from cells into the extracellular space [9,10]. Cells in the nephron constitutively release EVs under healthy conditions [11]
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