# TRIM27-controlled endothelium-derived exosomes play a central role in podocyte injury in diabetic kidney disease

## TL;DR

This study shows that exosomes from kidney endothelial cells contribute to podocyte injury in diabetic kidney disease, and targeting these exosomes could be a new treatment approach.

## Contribution

The study identifies TRIM27-controlled exosomes as a novel mediator of podocyte injury in diabetic kidney disease.

## Key findings

- High glucose and TGF-β1 increase exosome production by glomerular endothelial cells, causing podocyte injury.
- TRIM27 and miR-486-5p are key in exosome-mediated podocyte injury in diabetic kidney disease.
- Inhibiting exosome secretion or miR-486-5p reduces podocyte injury and proteinuria in diabetic mice.

## Abstract

Exosomes are extracellular vesicles involved in mediating cell–cell communication by shuttling genetic information and proteins. Here, we investigated whether glomerular endothelial cells-derived exosomes play a central role in mediating podocyte injury and proteinuria formation in diabetic kidney disease and its precise mechanism. In vitro, upon stimulation with high glucose and transforming growth factor-β1, primary human renal glomerular endothelial cells (HRGECs) produced more exosomes that directly mediated podocyte injury. Conversely, pharmacological inhibition of exosome secretion by GW4869, knockdown of tripartite motif-containing 27 (TRIM27) expression, or inhibition of miR-486-5p all abolished the ability of high glucose and transforming growth factor-β1-treated HRGECs to induce podocyte injury. In vivo, injections of HRGEC-derived exosomes aggravated podocyte injury and proteinuria in diabetic mice, which was negated by a miR-486-5p inhibitor. Furthermore, specific knockdown of TRIM27 expression or miR-486-5p in endothelial cells preserved kidney function and attenuated podocyte injury in diabetic mice. Thus, our results suggest that TRIM27-induced glomerular endothelial cell-derived exosomes play a major role in podocyte injury by shuttling miR-486-5p in diabetic kidney disease. Hence, strategies targeting exosomes may be a new direction in developing therapeutics for podocyte injury and proteinuria in diabetic kidney disease.