Objective To investigate the expression of miR-122 in the kidneys of diabetic nephropathy (DN) mice and the effect of miR-122 in the kidney of DN mice. Methods Streptozotocin ( STZ) intraperitoneal injection combined with a high-sugar and high-fat diet was used to establish the DN C57BL/ 6 mouse model. Thirty DN mice were randomly divided into the model group, antagomir-NC group and antagomir-122 group (10 / group). In addition, 10 healthy C57BL/ 6 mice without any treatment were selected as a normal control group. After the successful establishment of the model, the antagomir-122 and antagomir-NC groups were given tail vein injections of antagmir-122 and antagomir-NC every 7 days, and the model and normal control groups were given tail vein injections of the same volume of normal saline. After 8 weeks, serum and urine samples were collected and mice were sacrificed to obtain kidney specimens. An automatic biochemical analyzer was used to detect serum creatinine (Cr), blood urea nitrogen (BUN) and 24 h urine protein levels. Periodic acid schiff staining was used to evaluate renal histopathological changes, qRT-PCR was used to detect expression levels of miR-122 in renal tissue, and a kit was used to detect levels of glutathione peroxidase ( GSH-Px ), malondialdehyde (MDA), and superoxide dismutase (SOD) in renal tissues. Western blot was used to detect protein levels of Sirtuin 1 ( Sirt1), α-smooth muscle actin (α-SMA), and fibronectin in renal tissue. Results Compared with the normal control group, the glomerulosclerosis score of mice increased (P<0. 05), the expression of miR-122, α-SMA and fibronectin protein in renal tissue increased (P<0. 05), circulating levels of Cr and BUN, and quantitative levels of 24 h urine protein and MDA levels in renal tissue were all significantly increased (P<0. 05), and the expression levels of Sirt1 protein, and SOD and GSH-Px levels in renal tissue were all significantly reduced (P<0. 05) in the model group. There were no significant differences in the endpoints examined between the model group and antagomir-NC group. Compared with the antagomir-NC group, the glomerulosclerosis score, miR-122 expression, renal α-SMA and fibronectin protein levels, Cr and BUN levels, and 24 h urinary protein and renal tissue MDA levels were significantly decreased (P<0. 05), and renal tissue GSH-Px, SOD, and Sirt1 protein expression levels were significantly increased (P<0. 05) in the antagomir-122 group. Conclusions The expression of miR-122 was increased in kidneys of DN mice. Silencing miR-122 can protect renal tissues of DN mice from anti-oxidative stress and fibrosis, and its mechanism may be related to the regulation of Sirt1.