title: Angiotensin II increases the expression of the transcription factor ETS-1 in mesangial cells.
abstract: Maladaptive activation of the renin-angiotensin system (RAS) has been shown to play a critical role in the pathogenesis of chronic kidney disease. Reactive oxygen species (ROS) are critical signals for many of the nonhemodynamic effects of angiotensin II (ANG II). We have demonstrated that ANG II increases mesangial and cortical cyclooxygenase-2 (COX-2) expression and activity via NADPH oxidase-derived ROS. The transcription factor ETS-1 (E26 transformation-specific sequence) has been identified as a critical regulator of growth-related responses and inflammation. The present studies were designed to determine: 1) whether ANG II induces ETS-1 expression in vitro in cultured rat mesangial cells and in vivo in rats infused with ANG II; and 2) whether ROS and COX-2 are mediators of ETS-1 induction in response to ANG II. Mesangial cells stimulated with ANG II (10(-7) M) exhibited a significant increase in ETS-1 expression that was prevented by the angiotensin type 1 receptor blocker candesartan. NADPH oxidase inhibition with dyphenilene iodinium or apocynin also prevented ETS-1 induction, establishing the role of ROS as mediators of ETS-1 expression in response to ANG II. COX-2 inhibition prevented ETS-1 expression in response to ANG II, suggesting that COX-2 is required for ETS-1 induction. By utilizing short interfering RNAs against ETS-1, we have also determined that ETS-1 is required to induce the production of fibronectin in response to ANG II. Furthermore, rats infused with ANG II manifested increased glomerular expression of ETS-1. These studies unveil novel pathways that may play an important role in the pathogenesis of renal injury when RAS is activated.
authors.affiliation: The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Damien D
authors.initials: DD
authors.lastname: Pearse
authors.forename: Run-Xia
authors.initials: RX
authors.lastname: Tian
authors.forename: Jessica
authors.initials: J
authors.lastname: Nigro
authors.forename: Julian B
authors.initials: JB
authors.lastname: Iorgulescu
authors.forename: Leopold
authors.initials: L
authors.lastname: Puzis
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Jaimes
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000502:physiology; D005353:Fibronectins / Q000096:biosynthesis; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D050784:Proto-Oncogene Protein c-ets-1 / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C494043:Ets1 protein, rat; D005353:Fibronectins; D050784:Proto-Oncogene Protein c-ets-1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D000804:Angiotensin II; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C081643:candesartan