Reproducing human diabetic nephropathy in a novel obesity-driven animal model.

Abstract

Diabetic nephropathy is a leading cause of end-stage kidney disease worldwide, yet its complex pathogenesis remains incompletely understood. This is partly due to limitations of existing preclinical models, which are often genotypic, monogenic, and fail to replicate the chronic progression and advanced renal damage observed in humans. We previously developed a nongenotypic rat model of type 2 diabetes model using obese male Sprague Dawley rats chronically treated with low-dose tacrolimus, which reproduced key metabolic features of human type 2 diabetes. In this study, we investigated the onset and progression of diabetic nephropathy in this model. Glomerular filtration rate was measured by iohexol-dried blood sample (DBS) plasma clearance. Twenty-four-hour urine collection was performed to assess albuminuria and proteinuria. At the endpoint, kidneys were collected for histological evaluation. Tacrolimus blood levels were monitored monthly. Diabetic animals initially exhibited glomerular hyperfiltration, followed by a decline in glomerular filtration rate at the final stage of the study, consistent with the trajectory observed in humans. This was accompanied by a trend toward increased proteinuria. Histological analysis revealed mesangial matrix expansion, a higher incidence of glomeruli with focal segmental glomerulosclerosis and significant glomerular hypertrophy. In addition, we observed increased kidney weight, tubular hypertrophy, intraglomerular and tubulointerstitial fibrosis, and elevated cortical expression of proinflammatory markers. This model reproduced both early and advanced pathological features of human diabetic nephropathy, representing a valuable tool for studying diabetic nephropathy pathophysiology in a chronic context and as a platform for evaluating potential therapeutic strategies.We present a nongenotypic, obesity- and tacrolimus-induced rat model that recapitulates the chronic progression of human diabetic nephropathy. The model reproduces key early and advanced features, including hyperfiltration, glomerular filtration rate (GFR) decline, glomerular hypertrophy, mesangial expansion, nodular sclerotic lesions, and tubular-interstitial fibrosis. Its translational relevance and long-term progression provide a valuable platform for mechanistic studies and for evaluating potential therapeutic strategies.