The renin-angiotensin system plays a central role in the pathological mechanisms of diabetic nephropathy and is regulated by renal expression of cyclooxygenase-2 (COX-2). In the present study, the kidneys of diabetic KK-A^y mice, a model of human type 2 diabetes, were investigated histologically and immunohistochemically at 8, 12, 16, and 20 weeks of age, and changes in renal lesions and expression of COX-2 and renin were evaluated quantitatively. Glomerular damage, characterized by expansion of mesangial matrices and nodular lesions, was observed in the kidneys of these mice. The glomerular sclerosis score gradually increased with age and was significantly higher than those of age-matched control C57BL/6 mice at 12, 16, and 20 weeks of age. Although mild tubulointerstitial damage was observed, there was no significant change in the interstitial fibrosis score. These findings were considered early diabetic nephropathy changes. COX-2-positive signals were consistently detected in the macula densa cells of the thick ascending limbs in all KK-A^y mice, with a slightly higher score observed at 8 weeks of age. No COX-2-positive signals were detected in C57BL/6 mice. Renin-positive signals were commonly detected in the juxtaglomerular arterioles, and the scores in KK-A^y mice increased at 16 weeks and decreased at 20 weeks of age. The present study demonstrated activation of renal COX-2 and renin expression in diabetic KK-A^y mice at different stages. This finding suggests that these two enzymes contribute to the development and progression of diabetic nephropathy via different mechanisms.