ObjectiveTo establish a GK rat model of type 2 diabetic nephropathy induced by high-calorie and high-protein diet, and to explore its possible mechanism of action. MethodsA total of 24 28-week old GK rats were randomly divided into normal group and model group, 12 in each group. The normal rats were given normal diet while the model rats were fed a high-calorie and high-protein diet for 8 weeks. 24 h-U-ALB, 24 h-U-TP, Ucr, U-ALB/Ucr were determined at week 0,4, and 8. FBG, Scr, BUN, TC, TG, NO were measured at week 4 and 8. The rats were sacrificed 8 weeks later, and the two kidneys of each rat were taken and weighed to calculate the kidney hypertrophy index. The renal pathological changes were examined and the Na⁺K⁺-ATPase activity in renal tissue was detected. ResultsThe 24 h-U-ALB, 24 h-U-TP, U-ALB/Ucr, FBG, TC, TG, NO, kidney hypertrophy index and Na⁺K⁺-ATPase activity were significantly increased in the model group rats. They showed an increased glomerular volume of the kidney, mesangial matrix hyperplasia and thickening of the glomerular basement membrane. ConclusionsA GK rat model of type 2 diabetic nephropathy is successfully established by a high-calorie and high-protein diet. The rise in blood glucose and lipid levels contribute to the development of diabetic nephropathy. Besides, increased activity of Na⁺K⁺-ATPase further damages the function of renal tubules. The increased NO leads to glomerular hyperperfusion and hyperfiltration. These factors also accelerate the formation of nephropathy in GK rats. 