Tadehagi triquetrum aqueous extract ameliorates diabetic kidney disease through mitigating epithelial senescence via the PTEN/AKT/mTOR signaling pathway

Abstract Background Tadehagi triquetrum, a well-known medicinal plant widely consumed in Asia, possesses hypoglycemic properties. However, its precise impact in managing diabetic complications remains insufficiently understood. This study aims to investigate the protective effects and underlying mechanisms of T. triquetrum aqueous extract (TAE) on diabetic kidney disease (DKD). Methods The db/db mice were administered TAE at doses of 0.1, 0.2, and 0.4 g/kg for 10 weeks to assess its renoprotective effect. Senescence-associated β-galactosidase (SA-β-Gal) staining, Western blotting, and RT-qPCR were employed to assess the anti-senescence effects of TAE both in vivo and in vitro. RNA-seq was performed to uncover the molecular mechanisms through which TAE ameliorates tubular senescence. The involvement of PTEN/AKT/mTOR pathway was validated using shRNA-mediated gene knockdown in vitro and a pharmacological inhibitor of PTEN in vivo. UPLC-MS/MS analysis and molecular docking were used to identify active components targeting PTEN in TAE. Results TAE administration significantly improved renal function and attenuated histopathological damage in db/db mice. Additionally, TAE effectively suppressed cellular senescence in both in vivo and in vitro models, as evidenced by reduced SA-β-Gal-positive area, decreased levels of senescence-associated secretory phenotype, and downregulated expression of senescence-related proteins (P53, P21, and P16). RNA-seq analysis revealed that the anti-senescence effects of TAE were associated with the modulation of the mTOR signaling pathway. Validation experiments confirmed that TAE alleviates epithelial senescence by inhibiting PTEN-mediated activation of mTOR phosphorylation. UPLC-MS/MS analysis and molecular docking identified Hesperidin, Quercitrin, and Carnosol as major bioactive compounds in TAE with high binding affinity for PTEN. Conclusions In conclusion, our findings demonstrate that TAE exerts protective effects against epithelial senescence in DKD by modulating the PTEN/AKT/mTOR signaling, highlighting its potential as a novel therapeutic approach for the management of DKD. Graphical Abstract