{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:47:28Z","timestamp":1791920848812,"version":"4.3.4"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"publisher","award":["RR016469"],"award-info":[{"award-number":["RR016469"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alport syndrome (AS), a type IV collagen disorder, leads to glomerular disease and, in some patients, hearing loss. AS is treated with inhibitors of the renin\u2013angiotensin system; however, a need exists for novel therapies, especially those addressing both major pathologies. Sparsentan is a single\u2010molecule dual endothelin type\u2010A and angiotensin II type 1 receptor antagonist (DEARA) under clinical development for focal segmental glomerulosclerosis and IgA nephropathy. We report the ability of sparsentan to ameliorate both renal and inner ear pathologies in an autosomal\u2010recessive Alport mouse model. Sparsentan significantly delayed onset of glomerulosclerosis, interstitial fibrosis, proteinuria, and glomerular filtration rate decline. Sparsentan attenuated glomerular basement membrane defects, blunted mesangial filopodial invasion into the glomerular capillaries, increased lifespan more than losartan, and lessened changes in profibrotic\/pro\u2010inflammatory gene pathways in both the glomerular and the renal cortical compartments. Notably, treatment with sparsentan, but not losartan, prevented accumulation of extracellular matrix in the strial capillary basement membranes in the inner ear and reduced susceptibility to hearing loss. Improvements in lifespan and in renal and strial pathology were observed even when sparsentan was initiated after development of renal pathologies. These findings suggest that sparsentan may address both renal and hearing pathologies in Alport syndrome patients. \u00a9 2023 Travere Therapeutics, Inc and The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6087","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T11:45:40Z","timestamp":1685533540000},"page":"353-364","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice"],"prefix":"10.1002","volume":"260","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5512-7696","authenticated-orcid":false,"given":"Dominic","family":"Cosgrove","sequence":"first","affiliation":[{"name":"Center for Sensory Neuroscience Boys Town 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