Objective In the study,the effect of berberine on Diabetic Nephropathy (DN) via oxidative stress was studied.Methods The DN model mice was administered with metformin (0.2g/kg),low-dose berberine (0.036 g/kg),middle-dose berberine (0.072g/kg) and high-dose berberine (0.144g/kg) for 8 weeks.After that,the fasting glucose,insulin,serum creatinine,urea nitrogen,Reactive Oxidative Species (ROS),Superoxide Dismutase (SOD),Kelch-like ECH-associated protein 1 (Keap1) 、Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and NADPH oxidase 4 (NOX4),24h urine protein,etc were measured.Results Berberine could significantly decrease the fasting blood glucose levels,increase the insulin production,and reduce the levels of 24 h urine protein,serum urea nitrogen,creatinine,improve SOD and Nrf2,decrease ROS,Keap1and NOX4.Conclusion Berberine has the protactive effects in DN mice via the Keap-Nrf2/ARE pathway,and middle/high-dose berberine was much better.The mechanism may be related to the alleviated of the oxidative stress.