Abstract: SA-PO254
Quantitative Image Analysis Reveals the Benefits of Dapagliflozin on Glomerulosclerosis, Podocyte Effacement, and Kidney Fibrosis in the Spontaneously Diabetic Torii (SDT) Fatty Rat Model of Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - 2
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Briand, Francois, Physiogenex, Escalquens, France
- Grasset, Estelle, Physiogenex, Escalquens, France
- Shinohara, Masami, CLEA Japan Inc, Tokyo, Japan
- Endlich, Nicole, Nipoka, Greifswald, Germany
- Drenic, Vedran, Nipoka, Greifswald, Germany
- Chen, Li, Pharmanest, Princeton, New Jersey, United States
- Petitjean, Mathieu M., Pharmanest, Princeton, New Jersey, United States
- Dolicki, Blazej, Aiosyn, Nijmegen, Netherlands
- Bel, Thomas De, Aiosyn, Nijmegen, Netherlands
- Kageyama, Yasushi, CLEA Japan Inc, Tokyo, Japan
- Sulpice, Thierry, Physiogenex, Escalquens, France
Background
We aimed to optimize drug efficacy studies in the Spontaneously Diabetic Torii (SDT) fatty rat, a type 2 diabetic model, using quantitative image analysis of kidney. To demonstrate the accuracy of our imaging methods, dapagliflozin (DAPA) was evaluated in SDT fatty rats with unilateral nephrectomy (Unx).
Methods
Unx SDT fatty rats were fed a 0.3% salt diet and treated without or with DAPA for 10 weeks. Sham operated SDT fatty rats and Sprague Dawley (SD) rats were used as controls. Glomerular Filtration Rate (GFR) and urine parameters were measured at baseline, 5 weeks, and 10 weeks. Kidneys were collected at 10 weeks for histology and automated image analysis, including quantitative glomerulosclerosis and tubular impairments (Nephropath AI), Podocyte Exact Morphology Measurement Procedure (PEMP) and quantitative digital pathology of fibrosis (FibroNest platform).
Results
Sham rats showed higher proteinuria, urine albumin/creatinine ratio and KIM-1 levels (all p<0.05 vs SD). Those parameters were even higher in Unx rats (all p<0.01 vs sham). Hyperfiltration was only observed at baseline in sham rats (80% higher GFR, p<0.05 vs SD), 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 podocytes effacement, while FibroNest demonstrated significant increase in phenotypic fibrosis composite scores. All these imaging parameters were significantly aggravated in Unx rats.
DAPA significantly reduced hyperglycemia (-67% vs. untreated Unx rats), prevented the GFR decline (p<0.05 at 5 and 10 weeks) and reduced urine KIM-1 levels (p<0.01). DAPA significantly improved all imaging parameters and kidney inflammation (ED1 immunostaining).
Conclusion
Quantitative image analysis reveals the benefits of DAPA on glomerulosclerosis, podocytes effacement and kidney fibrosis in Unx SDT fatty rat. This experimental setting will help evaluating the efficacy of drugs targeting diabetic nephropathy.