Rac1 promotes exosome secretion from proximal renal tubules to accelerate DKD.

Chronic low-grade sterile inflammation is one hallmark of diabetic kidney disease (DKD). Exosomes secretion from renal cells plays an important role in the transmission of inflammatory substances, which is associated with DKD. Ras-related C3 botulinum toxin substrate 1 (Rac1) can promote renal morphologic abnormalities and dysfunction by eliciting secretion of inflammatory exosomes in renal tubular cells. However, whether and how Rac1 regulates exosomes secretion in DKD remains unclear. Here, we determined Rac1 major expression in proximal renal tubules, which positively correlated with exosomal marker proteins. Rac1 promotes the secretion of exosomes under high-glucose condition, and the exosomes derived from proximal renal tubular cells can be internalized and phagocytized by podocytes, further generating podocyte inflammatory damage. In proximal renal tubular cells, the inhibition or specific knockout of Rac1 can significantly reduce the secretion level of exosomes and the degree of inflammatory activation. Consequently, it can effectively decrease podocyte damage and improve renal function. Studies have found that Rac1 may collaborate with Rab8 and be involved in the transport process of exosomes, thereby promoting the secretion of exosomes. Moreover, the increased secretion of exosomes will further exacerbate the damage to podocytes. These findings have revealed a novel mechanism of exosome secretion in proximal renal tubular cells, which is expected to be a potential therapeutic target for diabetic kidney disease (DKD) in the future.