Next Generation of Spontaneous Diabetic Model of Fatzo Mice with Intact Leptin Signaling Develop Nephropathy after High-Fat and High-Sucrose Induction

Introduction: Progressive albuminuria and bi-phasic changes in glomular filtration rate (GFR) are hall marks of functional deterioration of the kidney in diabetic nephropathy. However, not all diabetic rodent models can capture the development of such changes in the kidney. FATZO, a new generation of diabetic mouse model with intact leptin signaling pathway shows all the metabolic dysfunctions that mimic human patients such as obesity, dyslipidemia, diabetes and NASH etc. Here, we sought to further characterize the model for the evaluation of its development in diabetic nephropathy. Method: Male FATZO mice on 50diet or on western diet with addition of 10% fructose (WD+fru) from age of 11 weeks were subject to monthly urine collection for albumin and creatinine measurement for 28 weeks, after which animals were treated with Lisinopril (15 mg/kg) and pioglitazone (20 mg/kg) daily for 6 weeks (n=8 for each group). Animals were also monitored for GFR using a subcutaneous monitoring device (Medibeacon, US). Results: Animals on WD+fru were heavier than those on 50diet. Notably, WD+fru markedly elevated urine albumin levels compared to 50diet in FATZO mice which resulted in higher albumin/creatinine ratio and urine albumin excretion rate (UAE) from 2 weeks on diet, while lisinopril treatment for 7 weeks could reduce the levels respectively. In addition, GFR was slightly elevated after 6 weeks of diet induction, which could be normalized by either pioglitazone or lisinopril treatment. Conclusion: We have created a mouse model with progressive albuminuria and elevated GFR that can be reversed by angiotensin-converting-enzyme (ACE) inhibitor. The model with associated dysmetabolic phenotypes including obesity and dyslipidemia can be used as an ideal tool for studying antidiabetic nephropathy treatment. Disclosure G. Sun: None. G. Zhang: None. Y. Wang: None.