Purpose: To investigate the effects of cannabinoid ligand in diabetic nephropathy mediated by streptozotocin (STZ) injection in rats. Methods: Rats deprived of food were injected streptozotocin (STZ, 70 mg/kg) followed by confirmation of diabetes by checking the blood glucose level for three consecutive days. The kidney tissue was exposed to periodic acid Schiff reagent (PASR) for the investigation of glomerular sclerotic injury under microscope. Results: Cannabinoid treatment decreased mesangial expansion, glomerular volume, proteinuria, reactive oxygen species and apoptosis in STZ rats. The cells were cultured with 40 mM of glucose for 8 h in which the podocytes responded with 2.9-fold increase in dihydroethidium fluorescence signal, compared to the podocytes cells cultured in low glucose (10 mM). However, cannabinoid treatment decreased ROS production in podocytes as indicated by dihydroehidium relative fluorescence. Further, the effect of ROS production by glucose on podocytes was inhibited by NADPH oxidase inhibitor, DPI (10 mM). Moreover, cannabinoid treatment reduced the expression of Sgk1, NADPH oxidase activity which was elevated by high glucose. Conclusion: Treatment with cannabinoid decreases mesangial expansion, glomerular volume, proteinuria, and reactive oxygen species production in STZ rats. Thus, cannabinoid may be a protective agent against diabetic nephropathy in humans.