Oral L-NAME supplementation accelerates the progression of kidney disease in diabetic mice

Background: Diabetic kidney disease (DKD) represents one of the leading causes of end-stage kidney disease (ESKD) worldwide. Given the global impact of DKD, numerous animal models have been designed and tested over the years in order to better understand and treat this disease. However, many of these DKD models exhibit slow progression, implementation challenges and maintenance issues. For this reason, we aimed to develop an accelerated and reproducible mouse model of DKD. Methods: For our experiments we opted for leptin receptor knock-out (C57BLKS/J Lepdb) mice as type 2 diabetes model. To aggravate kidney damage, we administered the endothelial nitric oxide synthase (eNOS) inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) in drinking water at 2 different concentrations (40 mg/kg/day and 80 mg/kg/day) for 6 weeks. Results: As early as 3 weeks, L-NAME treatment resulted in increased systolic blood pressure, accompanied by a significant decrease in glomerular filtration rate (GFR) and an increase in albumin-to-creatinine ratio. Periodic acid-Schiff (PAS) staining of kidney sections revealed that mice treated with 80 mg/kg/day of L-NAME developed enlarged glomeruli and mesangial expansion, while Wilms tumor protein (WT1) staining revealed a decrease in podocytes in the glomeruli. Moreover, Sirius red and collagen I stainings showed an increase of fibrotic tissue and collagen deposition in the kidneys. Conclusions: Taken together, our results demonstrate that L-NAME accelerates the progression of DKD in C57BLKS/J Lepdb mice, with detectable signs of kidney dysfunction after 3 weeks of treatment. Therefore, this model could be used to assess the therapeutic potential of novel interventions against DKD.