Objective To investigate the characteristics and differences between two type 2 diabetic model mice, db/db and KK-Ay, as models of diabetic nephropathy (DN), and to verify them with irbesartan treatment. Methods A total of 102 db/db and 102 KK-Ay mice (12 weeks old) were screened based on the albumin-tocreatinine ratio (ACR) and 24-hour urinary total protein (UCFP), with 78 mice of each strain selected and divided into 6 groups. The db/db + irbesartan group and KK-Ay + irbesartan group were administered irbesartan (40 mg/kg), the db/db group and KK-Ay group received an equal volume of drinking water for experimental animals, and the db/db + test article A groups and KK-Ay + test article A groups were given different doses of test article A (only the result of mortality data in the test articles groups were presented in the study, while other result were not shown). Wild-type C57BL/6J (WTa /WTb group) served as the normal control and were given experimental animal drinking water. Daily clinical observations were made, body mass was measured weekly, and ACR and UCFP were monitored periodically. At the end of administration, the mice were dissected, and the brain, liver, lungs and kidneys were collected, and the organ coefficients (organ mass×1000/body mass) were calculated. Blood was collected to measure serum total protein (TP), albumin (Alb),blood urea nitrogen (BUN), glucose (GLU), triglycerides (TG), and cholesterol (CHO). Kidney tissues were stained with HE, MASSON, and PAS to observe histopathological changes. Results Among the 78 KK-Ay mice, 5 died over 8 weeks, while among the 78 db/db mice, 21 died over 6 weeks. ACR increased with age in both the db/db and KK-Ay groups but decreased in the db/db+irbesartan and KK-Ay+irbesartan groups, though without statistical significance (P> 0.05). UCFP increased with age in the KK-Ay group but significantly decreased after irbesartan treatment (P<0.05). Compared with the WT groups, the kidney coefficients in the db/db and KK-Ay groups showed no significant changes (P>0.05), while the brain liver coefficients decreased significantly (P<0.01) and the liver coefficients increased significantly (P<0.01), but they did not change after irbesartan treatment (P>0.05). Compared with the WT groups, GLU and TG levels were significantly increased in the db/db and KK-Ay groups (P<0.01). Compared with the KK-Ay group, GLU and TG levels were significantly reduced in the KK-Ay+irbesartan group (P<0.01). In the db/db and KK-Ay groups, kidney tissues showed thickening of the glomerular mesangial matrix and mesangial cell proliferation, which were alleviated after irbesartan treatment. Conclusions Both 12-week-old db/db and KK-Ay mice can serve as models for DN research. Compared with db/db mice, KK-Ay mice exhibited smaller individual differences in ACR, fewer animal deaths after urine collection, and significant improvements in GLU, TG and UCFP after irbesartan treatment.