Endothelin-1 mediated induction of extracellular matrix genes in strial marginal cells underlies strial pathology in Alport mice

Daniel T. Meehan, Duane Delimont, Brianna Dufek, Marisa L Zallocchi, Grady Phillips, Michael Anne Gratton, Dominic E Cosgrove

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Alport syndrome, a type IV collagen disorder, manifests as glomerular disease associated with hearing loss with thickening of the glomerular and strial capillary basement membranes (SCBMs). We have identified a role for endothelin-1 (ET-1) activation of endothelin A receptors (ETARs) in glomerular pathogenesis. Here we explore whether ET-1 plays a role in strial pathology. Wild type (WT) and Alport mice were treated with the ETAR antagonist, sitaxentan. The stria vascularis was analyzed for SCBM thickness and for extracellular matrix (ECM) proteins. Additional WT and Alport mice were exposed to noise or hypoxia and the stria analyzed for hypoxia-related and ECM genes. A strial marginal cell line cultured under hypoxic conditions, or stimulated with ET-1 was analyzed for expression of hypoxia-related and ECM transcripts. Noise exposure resulted in significantly elevated ABR thresholds in Alport mice relative to wild type littermates. Alport stria showed elevated expression of collagen α1(IV), laminin α2, and laminin α5 proteins relative to WT. SCBM thickening and elevated ECM protein expression was ameliorated by ETAR blockade. Stria from normoxic Alport mice and hypoxic WT mice showed upregulation of hypoxia-related, ECM, and ET-1 transcripts. Both ET-1 stimulation and hypoxia up-regulated ECM transcripts in cultured marginal cells. We conclude that ET-1 mediated activation of ETARs on strial marginal cells results in elevated expression of ECM genes and thickening of the SCBMs in Alport mice. SCBM thickening results in hypoxic stress further elevating ECM and ET-1 gene expression, exacerbating strial pathology.

Original languageEnglish (US)
Pages (from-to)100-108
Number of pages9
JournalHearing Research
Volume341
DOIs
StatePublished - Nov 1 2016

Fingerprint

Endothelin-1
Extracellular Matrix
Basement Membrane
Pathology
Endothelin A Receptors
Genes
Extracellular Matrix Proteins
Noise
Hereditary Nephritis
Stria Vascularis
Collagen Type IV
Hearing Loss
Cultured Cells
Up-Regulation
Collagen
Hypoxia
Gene Expression
Cell Line
Proteins

Keywords

  • Alport syndrome
  • Basement membrane
  • Stria vascularis

ASJC Scopus subject areas

  • Sensory Systems

Cite this

Endothelin-1 mediated induction of extracellular matrix genes in strial marginal cells underlies strial pathology in Alport mice. / Meehan, Daniel T.; Delimont, Duane; Dufek, Brianna; Zallocchi, Marisa L; Phillips, Grady; Gratton, Michael Anne; Cosgrove, Dominic E.

In: Hearing Research, Vol. 341, 01.11.2016, p. 100-108.

Research output: Contribution to journalArticle

Meehan, Daniel T. ; Delimont, Duane ; Dufek, Brianna ; Zallocchi, Marisa L ; Phillips, Grady ; Gratton, Michael Anne ; Cosgrove, Dominic E. / Endothelin-1 mediated induction of extracellular matrix genes in strial marginal cells underlies strial pathology in Alport mice. In: Hearing Research. 2016 ; Vol. 341. pp. 100-108.
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AB - Alport syndrome, a type IV collagen disorder, manifests as glomerular disease associated with hearing loss with thickening of the glomerular and strial capillary basement membranes (SCBMs). We have identified a role for endothelin-1 (ET-1) activation of endothelin A receptors (ETARs) in glomerular pathogenesis. Here we explore whether ET-1 plays a role in strial pathology. Wild type (WT) and Alport mice were treated with the ETAR antagonist, sitaxentan. The stria vascularis was analyzed for SCBM thickness and for extracellular matrix (ECM) proteins. Additional WT and Alport mice were exposed to noise or hypoxia and the stria analyzed for hypoxia-related and ECM genes. A strial marginal cell line cultured under hypoxic conditions, or stimulated with ET-1 was analyzed for expression of hypoxia-related and ECM transcripts. Noise exposure resulted in significantly elevated ABR thresholds in Alport mice relative to wild type littermates. Alport stria showed elevated expression of collagen α1(IV), laminin α2, and laminin α5 proteins relative to WT. SCBM thickening and elevated ECM protein expression was ameliorated by ETAR blockade. Stria from normoxic Alport mice and hypoxic WT mice showed upregulation of hypoxia-related, ECM, and ET-1 transcripts. Both ET-1 stimulation and hypoxia up-regulated ECM transcripts in cultured marginal cells. We conclude that ET-1 mediated activation of ETARs on strial marginal cells results in elevated expression of ECM genes and thickening of the SCBMs in Alport mice. SCBM thickening results in hypoxic stress further elevating ECM and ET-1 gene expression, exacerbating strial pathology.

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