Introduction:
Our goal was to validate a rat model of IgA nephropathy for drug efficacy studies using quantitative image analysis of the kidney. To demonstrate the accuracy of our imaging methods, we evaluated atrasentan, a selective Endothelin A receptor Antagonist currently evaluated in phase III clinical trial.
Methods:
Wistar male rats received a single i.v. injection of Thy1.1 antibody on day 0 to induce IgA glomerulonephritis, and were then treated orally BID with vehicle or atrasentan 10mg/kg until day 7. A group of control rats were injected i.v. with PBS. 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 had significantly higher proteinuria, urine albumin/creatinine ratio (ACR), KIM-1 and cystatin-C levels at both day 2 and day 7, and a significantly lower GFR at day 7. Compared with vehicle, atrasentan did not improve GFR decline significantly, but markedly improved all urine parameters above.
Thy1.1 antibody injection led to a significantly higher kidney histopathological scoring (including greater proliferative glomerulonephritis, inflammation scores and tubule alterations), mean glomerular size and % alpha-SMA labelling, as compared to control. Compared with vehicle, all these parameters were again improved in rats treated with atrasentan.
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. Additionally, Kidney AI suite demonstrated significant increase in glomeruli with mesangial expansion in rats injected with Thy1.1, which was also significantly reduced by atrasentan.
Conclusions:
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.
The content of this abstract has been submitted to ASN Kidney Week 2024.
I have potential conflict of interest to disclose.
Employee and shareholder of Physiogenex
I did not use generative AI and AI-assisted technologies in the writing process.