Targeting to Intensify <scp>M2</scp> Macrophage Polarization Ameliorate Podocyte Lipid Accumulation and Damage by Tea Polyphenols via Activating <scp>SIRT1</scp> in the Aged Model Rats With <scp>DKD</scp>

Tea polyphenols (TP), as representative bioactive compounds of tea, exhibit anti-inflammatory and hypolipidemic effects on aging-associated Diabetic kidney disease (DKD), but the exact mechanism is unclear. Inflammation resulting from the dynamic imbalance of macrophage polarization and the injury of podocytes caused by lipid accumulation together drives the disease process. This study aims to explore the mechanism of TP alleviating aging with DKD via macrophage polarization and podocyte lipid accumulation. Initially, aging with DKD model rats were treated with or without TP (75, 150, 300 mg/kg once daily, ig) for 8 weeks; lipid accumulation in podocytes, inflammatory cytokines in serum and kidney, and macrophage phenotype in kidney were detected. We found silencing information regulator 1 (SIRT1), a key protein of cell senescence; its activation contributes to the transition of macrophages towards an anti-inflammatory phenotype. (-)-Epigallocatechin gallate (EGCG), the most important monomeric compound of TP, has been found to stably bind to SIRT1 by molecular docking experiment. Furthermore, an indirect co-culture system of RAW264.7 and MPC5 cells was constructed to investigate the effect of EGCG on the targeted macrophage polarization, ameliorating podocyte lipid accumulation. The agonist and inhibitor of SIRT1 were used to validate through immunofluorescence analysis, Oil Red O staining, lipid-related protein analysis, and phalloidin marking. We demonstrated that TP promotes SIRT1 activation, thereby enhancing the transformation of macrophages into the M2 phenotype, reducing renal inflammation, and ultimately alleviating podocyte lipid accumulation. Our study provides a new insight into the ways in which tea and its chemicals protect DKD in the elderly.