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Abstract: SA-PO576

The Dual AT1R/ETAR Blocker Sparsentan Slows Renal Disease, Improves Lifespan, and Prevents Hearing Loss in Alport Mice

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

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
  • Phillips, Grady, Washington University, St. Louis, Missouri, United States
  • Boettcher, Flint, Washington University, St. Louis, Missouri, United States
  • Hasson, James, Retrophin, Inc., San Diego, California, United States
  • Jenkinson, Celia P., Retrophin, Inc., San Diego, California, United States
  • Komers, Radko, Retrophin, Inc., San Diego, California, United States
  • Gratton, MichaelAnne, Washington University, St. Louis, Missouri, United States
Background

In Alport syndrome (AS), ETAR activation in mesangial cells results in subendothelial invasion of glomerular capillaries by mesangial filopodia and induction of inflammatory cytokines culminating in glomerulosclerosis (GS) and tubulointerstitial fibrosis (TIF). Hearing loss in AS is also a consequence of ETAR-mediated changes in the inner ear. We compared the effect of sparsentan (SP) with AT1R blocker losartan (LS) on the development of nephropathy and explored the effect of SP on hearing loss-associated inner ear pathology in Alport (AP) mice.

Methods

Wild type (WT) and AP mice were treated daily with vehicle (V), 120 mg/kg SP, or 10 mg/kg LS in 3 studies; early intervention (EI) from 3-7 weeks of age (W) (n=7-8), late intervention (LI) from 5-7W (n=8), or for lifespan (n=10). Proteinuria (UP/C) was assessed weekly, and immunostaining for fibronectin and collagen 1 was used to assess GS and TIF. Glomerular basement membrane dysmorphology was examined by electron microscopy (EM). For hearing, WT and AP mice were treated with V or SP in EI (n=5). Strial capillary basement membrane (SCBM) width was analyzed by EM. Hearing was assessed at 7W (n=5) by auditory brainstem response pre- and 5 days post-exposure to noise.

Results

SP or LS treatment in AP mice in EI (p<0.05 vs APV) attenuated increases in UP/C observed in APV at 7W and showed little to no TIF or GS. In LI, SP but not LS prevented a significant increase in GS compared to 5W untreated AP mice and significantly attenuated (p<0.05 vs APV 7W) UP/C and TIF compared to APV. Lifespan was significantly longer (p<0.05) for both SP- and LS-treated AP mice compared to APV. SP prevented both SCBM thickening and post-noise hearing loss at 16 kHz in AP mice (mean SCBM width±SD nm: 57.8±2.1 WTV, 67.6±5.5 APV, 54.7±2.4 APSP [p<0.05 APSP vs APV]; hearing loss: p<0.05 APSP vs APV).

Conclusion

In the LI studies, SP provided significant nephroprotection in AP mice, and to a greater extent than in the LS group. SP also significantly attenuated inner ear pathologies. Results from this study, if translated to the clinic, may present a therapeutic approach to reduction in both hearing and renal injury for AS patients.

Funding

  • Commercial Support – Retrophin, Inc., San Diego, CA