Abstract: OBJECTIVE To explore the potential mechanism of Xiaoyu Xiezhuo Decoction in preventing and treating renal fibrosis in diabetic nephropathy(DN) mice.METHODS The 60 db/db mice were used to prepare DN model and randomly divided into five groups including model group(equal volume saline), positive group(16 mg·kg^-1·d^-1 irbesartan), low dose, medium dose, and high dose of Xiaoyu Xiezhuo Decoction groups(7.5, 15, 30 g·kgm^-1·d^-1 Xiaoyu Xiezhuo Decoction), and 12 db/m mice of the same week age were selected as the control group(equal volume saline), the drug was administered by timed gavage for 8 weeks. The levels of fasting blood glucose(FBG), urinary creatinine(Ucr), microalbuminuria(mAlb), blood urea nitrogen(BUN), triglyceride(TG), total cholesterol(TC) and renal index of mice in each group were detected. HE, PAS and Masson staining were used to detect the pathological changes and the degree of renal fibrosis. Western blotting was used to detect the expression of α-smooth muscle actin(α-SMA), transforming growth factor β1(TGF-β1) and DNA methylation transferase1(DNMT1) in renal tissue, and immunohistochemistry was used to detect the expression of α-SMA and TGF-β1. RESULTS Compared with the control group, the levels of FBG, BUN, mAlb, TG and TC in blood and urine samples of DN mice in model group were significantly increased(P<0.01), while Ucr and renal index were significantly decreased(P<0.01). Compared with the model group, a certain dose of Xiaoyu Xiezhuo Decoction could significantly reduce the levels of FBG, BUN, mAlb, TG and TC, and increase the level of Ucr. The results of HE, PAS and Masson of kidney tissue staining showed that except for the low dose group of Xiaoyu Xiezhuo Decoction, the other treatment groups could reduce the glomerular volume, reduce the basement membrane thickness, alleviate the fibrous tissue hyperplasia symptoms and pathological damage. The improvement degree from high to low was positive group, high dose group and medium dose group of Xiaoyu Xiezhuo Decoction. In addition, medium and high dose of Xiaoyu Xiezhuo Decoction could significantly down regulate the protein expression levels of α-SMA, TGF-β1 and DNMT1 in the kidney tissues of DN mice, as well as the immunohistochemical expression of α-SMA and TGF-β1.CONCLUSION Xiaoyu Xiezhuo Decoction can inhibit the expression of DNMT1 and other renal fibrosis related factors, such as α-SMA and TGF-β1, and play an anti renal fibrosis role.