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Kidney Week

Abstract: FR-PO995

Sparsentan, a Dual Angiotensin II Type 1 (AT1) and Endothelin Type A (ETA) Receptor Antagonist, Prevents Renal Disease in COL4A3 -/- Autosomal Alport Mice

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Cosgrove, Dominic E., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Dufek, Brianna M., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Delimont, Duane C., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Meehan, Daniel T., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Samuelson, Gina C., Boys Town National Research Hospital, Omaha, Nebraska, United States
  • Liu, Kai, Retrophin, Inc., Portland, Oregon, United States
  • Jenkinson, Celia P., Retrophin, Inc., Portland, Oregon, United States
  • Armstrong, Bob, Retrophin, Inc., Portland, Oregon, United States
  • Komers, Radko, Retrophin, Inc., Portland, Oregon, United States
Background

Strain-mediated induction of endothelin (ET-1) in glomerular endothelial cells activates ETA receptors on mesangial cells, initiating invasion of glomerular capillaries by mesangial filopodia. The filopodia deposit matrix in the glomerular basement membrane resulting in stimulation of NFκB activity in podocytes and expression of pro-inflammatory cytokines, culminating in glomerulosclerosis and interstitial fibrosis. Both ETA receptor blockade and angiotensin-converting enzyme (ACE) inhibition have been shown to ameliorate these events in Alport mice. Therefore, we explored the ability of sparsentan to improve nephropathy in this model.

Methods

Alport mice were treated once daily with sparsentan (60 or 200 mg/kg given orally; n=3–4/group) or vehicle (n=4) from 3–7 weeks of age. Blood pressure (BP) and urinary protein/creatinine ratio (UP/C) were determined at the end of the study, together with determination of fibronectin and collagen 1 protein (COL1) immunohistochemistry (IHC) in kidney sections as an assessment of glomerulosclerosis and tubulointerstitial fibrosis.

Results

BP was not significantly different in Alport mice treated with sparsentan compared to vehicle at 7 weeks of age. Sparsentan led to significantly lower UP/C (60 mg: 5.6±3.0 mg/mg, n=4, P<0.05; 200 mg: 0.8±1.4 mg/mg, n=3, P<0.01) compared to vehicle-treated Alport mice (34.1±17.4 mg/mg, n=4). The percentage of sclerotic glomeruli, determined from fibronectin IHC was lower (P<0.01) in Alport mice that received sparsentan at 60 mg/kg (3.5±1.6%) or 200 mg/kg (1.4±1.3%) compared to vehicle-treated mice (39.0±19.5%). COL1 immunoreactivity was absent in sparsentan-treated Alport mice, similar to wild-type mice. In contrast, vehicle-treated Alport mice had a COL1 score of 2.5±0.6 (arbitrary units).

Conclusion

This preclinical study demonstrates that sparsentan, a dual ETA and AT1 receptor antagonist provides nephroprotection in Alport mice, in both glomerular and tubulointerstitial compartments. A further preclinical study is under way to explore the activity of sparsentan compared with ACE inhibition, the current standard of care in Alport renal disease.

Funding

  • Commercial Support