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Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice

ABSTRACT: Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice

PROVIDER: PRJNA951420 | ENA |

REPOSITORIES: ENA

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Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice

Project description:Alport syndrome, a type IV collagen disorder, leads to glomerular disease and, in some patients, hearing loss. AS is treated with inhibitors of the renin-angiotensin system; however, a need exists for novel therapies, especially those addressing both major pathologies. Sparsentan is a single-molecule dual endothelin type-A 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-recessive 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/proinflammatory genes pathways in both the glomerular and 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.

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Effects of endothelin A receptor blockade on renal interstitial disease in Alport mice

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Project description:Meniere's disease (MD), a syndromal inner ear disease, is commonly associated with a pathological accumulation of endolymphatic fluid in the inner ear, termed "idiopathic" endolymphatic hydrops (iEH). Although numerous precipitating/exacerbating factors have been proposed for MD, its etiology remains elusive. Here, using immunohistochemistry and in situ protein-protein interaction detection assays, we demonstrate mineralocorticoid-controlled sodium transport mechanisms in the epithelium of the extraosseous portion of the endolymphatic sac (eES) in the murine and human inner ears. Histological analysis of the eES in an extensive series of human temporal bones consistently revealed pathological changes in the eES in cases with iEH and a clinical history of MD, but no such changes were found in cases with "secondary" EH due to other otological diseases or in healthy controls. Notably, two etiologically different pathologies-degeneration and developmental hypoplasia-that selectively affect the eES in MD were distinguished. Clinical records from MD cases with degenerative and hypoplastic eES pathology revealed distinct intergroup differences in clinical disease presentation. Overall, we have identified for the first time two inner ear pathologies that are consistently present in MD and can be directly linked to the pathogenesis of EH, and which potentially affect the phenotypical presentation of MD.

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Alport syndrome in Romani

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Dual antagonism of the endothelin A and angiotensin II type 1 receptors protects from glomerular hypercellularity in a model of IgA nephropathy

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Endothelin signaling activates neural crest gene expression via a MEF2C-dependent positive-feedback transcriptional mechanism

Project description:Endothelin signaling is one of the essential signaling pathways that control vertebrate development. Dysregulated Endothelin signaling plays an important role in the pathogenesis of human diseases such as Hirschsprung’s disease, pulmonary hypertension and cancer. However, the downstream transcriptional program and transcriptional factors of Endothelin signaling have been incompletely understood. Here, we used RNA-sequencing to identify the genes regulated by Endothelin signaling in the neural crest, where Endothelin signaling functions primarily during development. We further demonstrate that Endothelin induces gene expression through the de-repression of the MADS Box transcription factor MEF2C. Moreover, in the Mef2c gene locus, we identified an Endothelin responsive cis-regulatory element which functions as a central component of an Endothelin-MEF2C positive feedback transcriptional mechanism that regulates downstream gene expression.

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