Abstract: SA-PO732
Quantitative Image Analysis Uncovers the Efficacy of the Selective Endothelin A Receptor Antagonist Atrasentan in a Rat Model of IgA Nephropathy
Session Information
- Glomerular Diseases: Therapeutic Strategies
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Briand, Francois, Physiogenex, Escalquens, France
- Grasset, Estelle, Physiogenex, Escalquens, France
- Endlich, Nicole, Nipoka, Greifswald, Germany
- Drenic, Vedran, Nipoka, Greifswald, Germany
- Dolicki, Blazej, Aiosyn, Nijmegen, Netherlands
- Bel, Thomas De, Aiosyn, Nijmegen, Netherlands
- Sulpice, Thierry, Physiogenex, Escalquens, France
Background
Our aim was to validate and optimize a rat model of IgA nephropathy for drug efficacy studies using quantitative image analysis of kidney. To demonstrate the accuracy of our imaging methods, we evaluated atrasentan, a selective Endothelin A receptor Antagonist currently evaluated in phase III clinical trials.
Methods
On day 0, Wistar male rats received a single i.v. injection of Thy1.1 antibody to induce IgA glomerulonephritis and were then treated orally BID with vehicle or atrasentan 10mg/kg until day 7. A group of rats were injected i.v. with PBS as control. Urine parameters were measured at day 2 and day 7, while Glomerular Filtration Rate (GFR) was measured at day 7. Kidneys were then collected for histology and automated image analysis, including quantitative mesangial expansion and tubular impairments (Kidney AI suite) and Podocyte Exact Morphology Measurement Procedure (PEMP).
Results
Compared to control, rats injected with Thy1.1 antibody showed significantly higher proteinuria, urine albumin/creatinine ratio (ACR), cystatin-C and KIM-1 levels at both day 2 and day 7, and significantly reduced GFR at day 7. Although it did not improve GFR decline significantly, atrasentan markedly improved all urine parameters above, as compared with vehicle.
Compared to control, Thy1.1 antibody injection also led to a significantly higher kidney histopathological scoring (including greater proliferative glomerulonephritis, inflammation scores and tubule alterations), mean glomerular size and % alpha-SMA labelling, and all these parameters were again improved with atrasentan treatment.
Filtration slit density and filtration slit length by PEMP were significantly reduced with Thy1.1 injection, indicating podocytes effacement, and both parameters increased in rats treated with atrasentan. Kidney AI suite demonstrated significant increase in glomeruli with mesangial expansion in rats injected with Thy1.1, which was also significantly reduced by atrasentan.
Conclusion
Quantitative image analysis uncovers the efficacy of atrasentan on glomerulonephritis in the Thy1.1 antibody rat model. This experimental setting will help evaluating the efficacy of drugs targeting IgA nephropathy.