MO033THE DUAL ETAR/AT1R BLOCKER SPARSENTAN SLOWS RENAL DISEASE, IMPROVES LIFESPAN, AND ATTENUATES HEARING LOSS IN ALPORT MICE: COMPARISON WITH LOSARTAN
| Autor: | Gina Samuelson, Ruth M. Gill, Celia Jenkinson, Duane Delimont, Radko Komers, Jared J. Hartsock, Grady Phillips, Dominic Cosgrove, Michael Anne Gratton, James Hasson, Daniel T. Meehan, Brianna Dufek |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Nephrology Dialysis Transplantation. 35 |
| ISSN: | 1460-2385 0931-0509 |
| Popis: | Background and Aims In Alport syndrome (AS), endothelin type A receptor (ETAR) activation plays a role in both renal and inner ear pathologies. Currently, angiotensin converting enzyme inhibitors or angiotensin II type 1 receptor (AT1R) blockers are the standard of care for patients with AS; however, these drugs have not been shown to improve hearing. Previously, we showed that sparsentan (SP), a dual ETAR/AT1R inhibitor, prevented increases in proteinuria, fibrosis, glomerulosclerosis, and glomerular basement membrane dysmorphology. The AS mouse model lifespan was extended when SP treatment was started at 3 weeks (W) of age (pre-proteinuric). Here we compare the effect of SP and the AT1R blocker losartan (LS) on lifespan and proteinuria in AS mice treated from 4 W, and on hearing loss and associated inner ear pathology in AS mice treated from 3 W to 8.75 W. Method Wild type (WT) and AS mice were treated daily with vehicle (V), 60, 120, or 200 mg/kg SP (SP60, SP120, or SP200) by oral gavage, or 20 mg/kg LS by daily oral gavage from 3-4 W of age and in drinking water at 10 mg/kg from 4-8.75 W. Three studies were conducted: early intervention for hearing from 3-8.75 W (V, SP120, and LS, n=5) or for assessment of laminin α2, laminin α5, and collagen IVα1 expression in stria vascularis from 3-7 W (V, SP200, and LS, n=7), and for lifespan with treatment from 3 W (V, n=10) or from 4 W (LS, SP60, or SP120, n=5). Urinary protein/creatinine (UP/C) was assessed weekly during the lifespan study. In the hearing study, the auditory brainstem response (ABR) assessed hearing ability and sensitivity to noise at 8-9 W (n=5). The cochleae were preserved and transmission electron microscopy was used to assess severity of strial pathology and to measure strial capillary basement membrane (SCBM) thickness (n=5-7). Accumulation of extracellular matrix in SCBM was determined in mice treated with V, SP200, or LS by immunofluorescence microscopy using antibodies to laminin α2, laminin α5, or collagen IVα1. Results In AS mice treated with SP from 4 W, SP120 significantly (P Conclusion SP120 provided significant nephroprotection in AS mice when treatment was started at 4 W, significantly extending lifespan beyond that of mice treated with LS while delaying the development of proteinuria. SP120 treatment in AS mice reduced the SCBM width. Moreover, SP120 treatment significantly attenuated noise-induced hearing loss in AS mice whereas LS was without effect. These pre-clinical studies, if successfully translated to the clinic, may suggest that sparsentan offers a novel, dual-therapeutic approach in AS by reducing both renal injury and hearing loss. |
| Databáze: | OpenAIRE |
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