A Novel Diabetes Mellitus Mouse Model, MAFA-Deficient and Beta Cell-Specific MAFK-Overexpressing Hybrid Transgenic Mice, Developed Severe Diabetic Nephropathy and Improved with TCV-116 (Candesartan Cilexetil) Treatment

Abstract

Many models of diabetic nephropathy have been reported. However, it is rare that the characteristic findings of severe human diabetic nephropathy, such as diffuse, nodular, and exudative lesions, are all detected in one model mouse. Previously, we reported that MAFA-deficient and beta cell-specific MAFK-overexpressing hybrid transgenic (Mafa(-/-)Mafk (+)) mice develop diabetes mellitus and, after uninephrectomy, demonstrate these characteristic lesions. In this study, we administered TCV-116 (candesartan cilexetil) to Mafa(-/-)Mafk (+) mice after uninephrectomy and examined whether TCV-116 ameliorated the diabetic nephropathy. We also evaluated the utility of these mice as a model for developing treatments for diabetic nephropathy. We performed uninephrectomy of the Mafa(-/-)Mafk (+) mice at 8 weeks old. We then divided these mice into two groups as follows: 1) an untreated group and 2) a group treated with TCV-116 at 5 µg/g/day from 10 to 20 weeks. TCV-116 treatment did not affect serum glucose levels. However, in the treated group, urinary protein excretion, mesangial matrix expansion, enlargement of the kidney, and glomerular surface area were all improved relative to untreated mice. Oxidative stress is known to be increased in diabetic nephropathy and to be suppressed by TCV-116. The urinary level of 8-OHdG, an oxidative stress marker, at 20 weeks was lower in the TCV-116-treated group than in the untreated group. From these results, we concluded that the Mafa(-/-)Mafk (+) mouse is a useful model to analyze diabetic nephropathy and a useful tool for the development of new drugs to treat diabetic nephropathy.