Triptolide promotes autophagy to protect renal tubular epithelial cells from high glucose-induced macrophage-derived exosomes incubation.

Diabetic kidney disease (DKD) is a leading cause of kidney failure. It is characterized by damage to renal tubular endothelial cells, which is exacerbated by macrophage-derived exosomes under high-glucose (HG) conditions. Triptolide (TPL), an active ingredient extracted from Tripterygium wilfordii Hook F, has been used in the treatment of DKD. In this study, we aimed to investigate whether TPL protects against renal damage induced by macrophage-derived exosomes under HG conditions and to explore the involvement of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathway in this process. Exosomes were isolated from macrophages cultured in normal glucose (NG) and HG environments and characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Subsequent in vitro experiments on mouse renal tubular epithelial cells (mRTECs) demonstrated that 5 ng/mL TPL enhanced cell viability, reduced apoptosis and inflammation, and promoted autophagy-effects that were reversed by the autophagy inhibitor chloroquine (CQ). Molecular docking and bioinformatic analyses suggested a stable interaction between TPL and AKT, implicating the AKT/mTOR pathway in TPL-mediated autophagy activation. Further in vivo studies using an AKT agonist supported the role of TPL in inhibiting AKT/mTOR signaling and enhancing autophagic activity, ultimately ameliorating renal injury in a DKD model. These findings provide novel insights into the mechanisms by TPL may mitigate exosome-induced renal damage, highlighting its potential as a therapeutic agent for DKD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10616-025-00883-8.