The Dual Endothelin/Angiotensin II Receptor (ETAR/AT1R) Antagonist Sparsentan Slows Renal Disease, Improves Lifespan, and Attenuates Hearing Loss in Alport Mice: Comparison with Losartan and Atrasentan

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Background: In Alport syndrome (AS), ETAR activation is important in renal and inner ear pathologies. Previously, sparsentan (SP) was shown to prevent increases in proteinuria, glomerulosclerosis, and glomerular basement membrane dysmorphology in AS mice. Here we compare the effect of SP, the AT1R antagonist losartan (LS), and the ETAR antagonist atrasentan (ATR) on lifespan and proteinuria, and of SP and LS on hearing loss and inner ear pathology. Methods: Wild type (WT) and AS mice were gavaged daily with vehicle (V), 60 or 120 mg/kg of SP (SP60, SP120), LS (20 mg/kg; 3-4 W) or LS (10 mg/kg from 4 W), or ATR (7.5 mg/kg females or 10 mg/kg males) in the drinking water. Two studies were conducted: early intervention for hearing from 3-8.75 W (V, SP120 and LS), and for lifespan with treatment from 3 W (V) or from 4 W (SP60, SP120, LS or ATR). Urinary protein/creatinine ratio (UP/C) was assessed weekly. The auditory brainstem response (ABR) was used to assess hearing ability and sensitivity to noise at 8-8.75 W. The cochleae were preserved and strial pathology determined by transmission electron microscopy. Results: SP120 significantly (P<0.05) increased median lifespan compared to any other group (Figure 1). At 8 W, only SP120 significantly (P<0.05) attenuated the increase in UP/C compared to V (UP/C mg/mg mean±SD: 47±16 V; 31±6 LS; 42±18 ATR, 61±44 SP60; 20±3 SP120). UP/C at 11 W in SP120 mice was significantly attenuated (P<0.05) vs. LS mice. SP120 significantly improved post-noise ABR thresholds at 16 kHz vs. V mice (P<0.05), LS had no effect. Dysmorphology of the stria vascularis was noted in LS but not SP120-treated mice. Conclusions: SP120 in AS mice extended lifespan beyond that of mice treated with SP60, LS, or ATR and attenuated noise-induced hearing loss compared to LS. Sparsentan may therefore offer a novel, dual-therapeutic approach in AS by reducing both renal injury and hearing loss. Funding: Commercial Support - Retrophin, Inc.

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