title: Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease.
abstract: Recent work demonstrates that Alport glomerular disease is mediated through a biomechanical strain-sensitive activation of mesangial actin dynamics. This occurs through a Rac1/CDC42 cross-talk mechanism that results in the invasion of the subcapillary spaces by mesangial filopodia. The filopodia deposit mesangial matrix proteins in the glomerular basement membrane, including laminin 211, which activates focal adhesion kinase in podocytes culminating in the up-regulation of proinflammatory cytokines and metalloproteinases. These events drive the progression of glomerulonephritis. Here we test whether endothelial cell-derived endothelin-1 is up-regulated in Alport glomeruli and further elevated by hypertension. Treatment of cultured mesangial cells with endothelin-1 activates the formation of drebrin-positive actin microspikes. These microspikes do not form when cells are treated with the endothelin A receptor antagonist sitaxentan or under conditions of small, interfering RNA knockdown of endothelin A receptor mRNA. Treatment of Alport mice with sitaxentan results in delayed onset of proteinuria, normalized glomerular basement membrane morphology, inhibition of mesangial filopodial invasion of the glomerular capillaries, normalization of glomerular expression of metalloproteinases and proinflammatory cytokines, increased life span, and prevention of glomerulosclerosis and interstitial fibrosis. Thus endothelin A receptor activation on mesangial cells is a key event in initiation of Alport glomerular disease in this model.
authors.affiliation: Center for Basic Research, Boys Town National Research Hospital, Omaha, Nebraska, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Dufek
authors.affiliation: Center for Basic Research, Boys Town National Research Hospital, Omaha, Nebraska, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meehan
authors.affiliation: Center for Basic Research, Boys Town National Research Hospital, Omaha, Nebraska, USA.
authors.forename: Duane
authors.initials: D
authors.lastname: Delimont
authors.affiliation: Center for Basic Research, Boys Town National Research Hospital, Omaha, Nebraska, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Cheung
authors.affiliation: Department of Otolaryngology, Saint Louis University, St. Louis, Missouri, USA.
authors.forename: Michael Anne
authors.initials: MA
authors.lastname: Gratton
authors.affiliation: Department of Otolaryngology, Saint Louis University, St. Louis, Missouri, USA.
authors.forename: Grady
authors.initials: G
authors.lastname: Phillips
authors.affiliation: Sanofi-Genzyme Research and Development Center, Framingham, Massachusetts, USA.
authors.forename: Wenping
authors.initials: W
authors.lastname: Song
authors.affiliation: Sanofi-Genzyme Research and Development Center, Framingham, Massachusetts, USA.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Center for Basic Research, Boys Town National Research Hospital, Omaha, Nebraska, USA. Electronic address: Dominic.cosgrove@boystown.org.
authors.forename: Dominic
authors.initials: D
authors.lastname: Cosgrove
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D019332:Endothelin-1 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D050533:Glomerular Basement Membrane / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D007797:Laminin / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009394:Nephritis, Hereditary / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000188:drug therapy; D011554:Pseudopodia / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; D007797:Laminin; D034741:RNA, Small Interfering; D044022:Receptor, Endothelin A; D013876:Thiophenes; C106276:sitaxsentan
keywords: Alport syndrome; actin dynamics; endothelin; glomerulonephritis