title: Progressive endothelin-1 gene activation initiates chronic/end-stage renal disease following experimental ischemic/reperfusion injury.
abstract: This study assessed whether endothelin-1 (ET-1) helps mediate postischemic acute kidney injury (AKI) progression to chronic kidney disease (CKD). The impact(s) of potent ETA or ETB receptor-specific antagonists (Atrasentan and BQ-788, respectively) on disease progression were assessed 24 h or 2 weeks following 30 min of unilateral ischemia in CD-1 mice. Unilateral ischemia caused progressive renal ET-1 protein/mRNA increases with concomitant ETA, but not ETB, mRNA elevations. Extensive histone remodeling consistent with gene activation and increased RNA polymerase II (Pol II) binding occurred at the ET-1 gene. Unilateral ischemia produced progressive renal injury as indicated by severe histologic injury and a 40% loss of renal mass. Pre- and post-ischemia or just postischemic treatment with Atrasentan conferred dramatic protective effects such as decreased tubule/microvascular injury, normalized tissue lactate, and total preservation of renal mass. Nuclear KI-67 staining was not increased by Atrasentan, implying that increased tubule proliferation was not involved. Conversely, ETB blockade had no protective effect. Thus, our findings provide the first evidence that ET-1 operating through ETA can have a critical role in ischemic AKI progression to CKD. Blockade of ETA provided dramatic protection, indicating the functional significance of these results.
authors.affiliation: 1] The Department of Medicine, University of Washington, Seattle, Washington, USA [2] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
authors.forename: Ali C M
authors.initials: AC
authors.lastname: Johnson
authors.forename: Dennis
authors.initials: D
authors.lastname: Andress
authors.forename: Kirsten
authors.initials: K
authors.lastname: Becker
mesh_terms: D000818:Animals; D000077868:Atrasentan; D004195:Disease Models, Animal; D018450:Disease Progression; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics* / Q000502:physiology*; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000502:physiology; D044023:Receptor, Endothelin B / Q000187:drug effects / Q000502:physiology; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000503:physiopathology*; D015427:Reperfusion Injury / Q000150:complications / Q000503:physiopathology*
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010880:Piperidines; D011759:Pyrrolidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C086539:BQ 788; D000077868:Atrasentan