Objective To investigate the characteristics and differences of db/db and KK-Ay mice as diabetic nephropathy (DN) model, and to verify them with Irbesartan treatment. Methods 102 db/db and 102 KK-Ay mice at 12 weeks of age were selected and grouped based on urine ACR (ratio of microalbuminuria MAU and CRE) and UCFP (24-hour total urine protein), then they were given Irbesartan (40mg?kg-1), experimental animal drinking water (model group), and other test articles, with 13 mice in each group. Wild type C57BL/6J (WT) was used as normal control group. Clinical observation was performed daily and mice were weighed every week, together with irregular monitoring of ACR and UCFP. At the end of administration, brain, liver, lung and kidneys were dissected and weighed, organ coefficients were calculated (organ weight ×1000/ animal body weight). Blood was collected and serum TP, Alb, BUN, GLU, TG and CHO were detected. The histopathological changes of renal tissue were observed by HE, MASSON and PAS staining. Results A total of 5 KK-Ay died in 8 weeks and 21 db/db died in 6 weeks;ACR increased with age in db/db and KK-Ay groups, but decreased in Irbesartan groups without statistical difference (p>0.05); UCFP increased with age in KK-Ay group and decreased significantly after Irbesartan treatment (p?0.05); Compared with WT, renal coefficients of db/db and KK-Ay mice had no significant changes (p>0.05), liver coefficients increased significantly (p?0.01), head coefficients decreased significantly (p?0.01), but they did not change after Irbesartan treatment (p>0.05); Compared with WT, serum GLU and TG of db/db and KK-Ay mice were significantly increased (p?0.01), but only that of KK-Ay mice were significantly decreased after Irbesartan treatment (p?0.01); Both db/db and KK-Ay kidneys showed an increase in mesangial matrix and mesangial cells proliferation, and the lesion degree was reduced in the Irbesartan treatment groups. Conclusion Both db/db and KK-Ay at 12 weeks of age can be used as DN models. Compared with db/db, KK-Ay mice have smaller individual differences in ACR and MAU, fewer animal deaths after urine collection, and significant improvements in GLU and TG after treatment, making it more suitable for studying the efficacy and mechanism of DN.