Hederagenin attenuates renal senescence in diabetic kidney disease by inhibiting DNMT1- mediated Klotho DNA methylation

Renal senescence plays a crucial role in the development of diabetic kidney disease (DKD). The progression of DKD can accelerate the senescence process of the kidney, making it more susceptible to diabetes-induced damage and accelerating the process of renal fibrosis. However, there is no effective treatment for this pathological process. Hederagenin (Hed) has shown promising improvements in renal fibrosis in chronic kidney disease and DKD, but its mechanism in DKD-induced renal senescence remains unclear. In this study, we found that Hed exhibited significant anti-renal senescence effects in palmitic acid-induced HK-2 cell senescence and in the kidneys of db/db mice. Additionally, through the GEO database, we discovered that Klotho is significantly downregulated in patients with DKD, and Hed can restore the expression of Klotho in senescence HK-2 cells and the kidneys of db/db mice. We utilized molecular docking, molecular dynamics simulation and surface plasmon resonance to find that Hed can bind to DNMT1. CHIP-qPCR experiments revealed that Hed competitively inhibits the binding of DNMT1 to the Klotho promoter region. Collectively, our study demonstrates that Hed possesses anti-renal senescence effects by interfering with the DNMT1-mediated Klotho DNA methylation process, thereby restoring Klotho expression and reducing DNA damage. These findings provide new mechanistic insights into the therapeutic potential of Hed in the treatment of DKD.