title: Endothelin-1 mediated induction of extracellular matrix genes in strial marginal cells underlies strial pathology in Alport mice.
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.
authors.affiliation: Boys Town National Research Hospital, Omaha, NE, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meehan
authors.affiliation: Boys Town National Research Hospital, Omaha, NE, USA.
authors.forename: Duane
authors.initials: D
authors.lastname: Delimont
authors.affiliation: Boys Town National Research Hospital, Omaha, NE, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Dufek
authors.affiliation: Boys Town National Research Hospital, Omaha, NE, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Zallocchi
authors.affiliation: Saint Louis University, St. Louis, MO, USA.
authors.forename: Grady
authors.initials: G
authors.lastname: Phillips
authors.affiliation: Saint Louis University, St. Louis, MO, USA.
authors.forename: Michael Anne
authors.initials: MA
authors.lastname: Gratton
authors.affiliation: Boys Town National Research Hospital, Omaha, NE, USA; University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: Dominic.cosgrove@boystown.org.
authors.forename: Dominic
authors.initials: D
authors.lastname: Cosgrove
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D001831:Body Temperature; D002196:Capillaries / Q000473:pathology; D002460:Cell Line; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics*; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000473:pathology; D007555:Isoxazoles / Q000737:chemistry; D007797:Laminin / Q000378:metabolism; D051379:Mice; D009394:Nephritis, Hereditary / Q000503:physiopathology*; D018384:Oxidative Stress; D010641:Phenotype; D013316:Stria Vascularis / Q000166:cytology* / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry
chemical_list: D024141:Collagen Type IV; D019332:Endothelin-1; D007555:Isoxazoles; D007797:Laminin; D013876:Thiophenes; C102645:laminin alpha 2; C097043:laminin alpha5; C106276:sitaxsentan
keywords: Alport syndrome; Basement membrane; Stria vascularis