We aimed to optimize drug efficacy studies in the Spontaneously Diabetic Torii (SDT) fatty rat, a type 2 diabetic model, using kidney histology image analysis with 1) quantitative glomerulosclerosis and tubular impairments (Nephropath AI), 2) Podocyte Exact Morphology Measurement Procedure (PEMP) and 3) quantitative digital pathology of fibrosis (FibroNest platform). To demonstrate the potential of our imaging methods, dapagliflozin for 10 weeks was evaluated in SDT fatty rats fed a 0.3% salt diet with unilateral nephrectomy (Unx). Sham operated SDT fatty and Sprague Dawley (SD) rats were used as controls. Sham rats showed higher urine albumin/creatinine ratio and KIM-1 levels (all p<0.05 vs SD). Those parameters were further elevated in Unx rats (all p<0.01 vs sham). Significant hyperfiltration was only observed at baseline in sham rats, while Unx rats showed a significant GFR decline from baseline to 10 weeks. In sham rats, Nephropath AI demonstrated higher number of dilated/atrophic tubuli and sclerotic glomeruli (all p<0.01 vs SD). Filtration slit density and filtration slit length measured by PEMP were significantly reduced, indicating podocyte effacement, while FibroNest demonstrated significant increase in phenotypic fibrosis composite scores. All these imaging parameters were significantly aggravated in Unx rats. Dapagliflozin significantly reduced hyperglycemia, urine KIM-1 levels and prevented GFR decline. Dapagliflozin significantly improved most of the imaging parameters and kidney inflammation (ED1 immunostaining). Quantitative image analysis reveals the benefits of dapagliflozin on glomerulosclerosis, podocyte effacement and kidney fibrosis in Unx SDT fatty rat. This experimental setting will help evaluating the efficacy of drugs targeting diabetic nephropathy.
Briand et al. (Mon,) studied this question.
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