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

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.