To investigate the therapeutic effects and mechanisms of Zishen Tongguan Prescription on improving renal damage in diabetic rats.Methods:Fifty 8-week-old male SD rats were randomly divided into five groups(n=10)，i.e.，control group，model group，and Zishen Tongguan Prescription low-dose(7.0 g/kg for crude drug)，medium-dose(14.0 g/kg for crude drug)，and high-dose(28.0 g/kg for crude drug) groups.Except for the control group，the rats in the other groups were fed on a high-fat and high-sugar diet for 4 weeks and then injected intraperitoneally with streptozotocin(STZ，35 mg/kg) to induce diabetic nephropathy model.After successful modeling，the rats in each group were orally administered the corresponding drugs or normal saline for 4 weeks，once a day.Fasting blood glucose(FBG)，serum urea nitrogen(BUN)，creatinine(Cr)，total cholesterol(TC)，and triglycerides(TG) levels were measured before and 1，2，3，and 4 weeks after administration.Enzyme-linked immunosorbent assay(ELISA) was used to detect serum tumor necrosis factor-alpha(TNF-α)，interleukin-6(IL-6)，and interleukin-1β(IL-1β) levels.Kidney damage was observed using hematoxylin-eosin(HE) staining，and the expression of transforming growth factor-β1(TGF-β1)/Smads pathway-related proteins in kidney tissues was detected using Western blot.Results:Compared with the control group，the rats in the model group showed significantly elevated FBG，serum BUN，Cr，TC，TG，TNF-α，IL-6，and IL-1β levels(all P<0.05)，as well as pathological changes in kidney tissues.The expression of TGF-β1，Smad3，α-smooth muscle actin(α-SMA)，and Vimentin was significantly upregulated，while the expression of Smad7 was significantly downregulated.After 4 weeks of treatment with Zishen Tongguan Prescription at low，medium，and high doses，the levels of FBG，serum BUN，Cr，TC，TG，TNF-α，IL-6，and IL-1β in diabetic nephropathy rats were significantly decreased(all P<0.05)，and kidney tissue pathology was significantly improved.The expression of TGF-β1，Smad3，α-SMA，and Vimentin was downregulated，while the expression of Smad7 was upregulated.The effects of Zishen Tongguan Prescription in different dose groups showed a certain dose-dependent relationship.Conclusion:Zishen Tongguan Prescription can improve diabetic nephropathy by inhibiting the TGF-β1/Smads signaling pathway.