Rutin alleviates EndMT by restoring autophagy through inhibiting HDAC1 via PI3K/AKT/mTOR pathway in diabetic kidney disease

Background: Diabetic kidney disease (DKD) is a primary microvascular complication of diabetes. However, a complete cure for DKD has not yet been found. Although there is evidence that Rutin can delay the onset of DKD, the underlying mechanism remains unclear. Purpose: To investigate the renoprotective effect of Rutin in the process of DKD and to explore its potential molecular mechanisms. Methods: Db/db mice and high glucose (HG)-induced human renal glomerular endothelial cells (GEnCs) were used as in vivo and in vitro models, respectively. Western blot (WB), Immunohistochemistry (IHC)and Immu-nofluorescence (IF) staining were used to identify the expression level of proteins associated with endothelial-to-mesenchymal transition (EndMT) and autophagy. Tandem Mass Tag (TMT)-based proteomics analysis was uti-lized to reveal the mechanism of Rutin in DKD. Transfection with small interfering RNA (siRNA) to reveal the role of histone deacetylase 1 (HDAC1) in HG-induced GEnCs. Results: Following 8 weeks of Rutin administration, db/db mice's kidney function and structure significantly improved. In HG-induced GEnCs, activation of autophagy attenuates cellular EndMT. Rutin could alleviate EndMT and restore autophagy in vivo and in vitro models. Proteomics analysis results showed that HDAC1 significantly downregulated in the 200 mg/kg/d Rutin group compared with the db/db group. Transfection with si-HDAC1 in GEnCs partially blocked HG-induced EndMT and restored autophagy. Furthermore, Rutin inhibits the phosphorylation of the PI3K / AKT/ mTOR pathway. HDAC1 overexpression was suppressed in HG-induced GEnCs after using Rapamycin, a specific mTOR inhibitor, verifying the correlation between mTOR and HDAC1. Conclusion: Rutin alleviates EndMT by restoring autophagy through inhibiting HDAC1 via the PI3K/AKT/mTOR pathway in DKD.

Automated summary

This study aimed to investigate the renoprotective effect of Rutin in diabetic kidney disease (DKD) and explore its potential molecular mechanisms. The results showed that Rutin can improve kidney function and structure in DKD by restoring autophagy through inhibiting HDAC1 via the PI3K/AKT/mTOR pathway, thereby alleviating endothelial-to-mesenchymal transition (EndMT). These findings have important implications for the treatment and prevention of DKD.