title: The transcription factor ETS-1 regulates angiotensin II-stimulated fibronectin production in mesangial cells.
abstract: Angiotensin II (ANG II) produced as result of activation of the renin-angiotensin system (RAS) plays a critical role in the pathogenesis of chronic kidney disease via its hemodynamic effects on the renal microcirculation as well as by its nonhemodynamic actions including the production of extracellular matrix proteins such as fibronectin, a multifunctional extracellular matrix protein that plays a major role in cell adhesion and migration as well as in the development of glomerulosclerosis. ETS-1 is an important transcription factor essential for normal kidney development and glomerular integrity. We previously showed that ANG II increases ETS-1 expression and is required for fibronectin production in mesangial cells. In these studies, we determined that ANG II induces phosphorylation of ETS-1 via activation of the type 1 ANG II receptor and that Erk1/2 and Akt/PKB phosphorylation are required for these effects. In addition, we characterized the role of ETS-1 on the transcriptional activation of fibronectin production in mesangial cells. We determined that ETS-1 directly activates the fibronectin promoter and by utilizing gel shift assays and chromatin immunoprecipitation assays identified two different ETS-1 binding sites that promote the transcriptional activation of fibronectin in response to ANG II. In addition, we identified the essential role of CREB and its coactivator p300 on the transcriptional activation of fibronectin by ETS-1. These studies unveil novel mechanisms involved in RAS-induced production of the extracellular matrix protein fibronectin in mesangial cells and establish the role of the transcription factor ETS-1 as a direct mediator of these effects.
authors.affiliation: Division of Nephrology, University of Alabama at Birmingham, 1530 3rd Ave. South, Birmingham, AL 35294-1150, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Hua
authors.forename: Wenguang
authors.initials: W
authors.lastname: Feng
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rezonzew
authors.forename: Phillip
authors.initials: P
authors.lastname: Chumley
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Jaimes
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D050881:E1A-Associated p300 Protein / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005353:Fibronectins / Q000096:biosynthesis*; D017930:Genes, Reporter / Q000235:genetics; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047468:Immunoprecipitation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000502:physiology*; D051381:Rats; D013268:Stimulation, Chemical; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005353:Fibronectins; D050784:Proto-Oncogene Protein c-ets-1; D000804:Angiotensin II; D050881:E1A-Associated p300 Protein; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases