title: Lack of an apparent role for endothelin-1 in the prolonged reduction in renal perfusion following severe unilateral ischemia-reperfusion injury in the mouse.
abstract: Therapeutic approaches to block the progression from acute kidney injury to chronic kidney disease are currently lacking. Endothelin-1 (ET-1) is a powerful vasoconstrictor, induced by hypoxia, and previously implicated in renal ischemia-reperfusion (IR) injury. This study tested the hypothesis that blunting the vascular influence of ET-1, either through endothelin ETAreceptor blockade (ABT-627) or vascular endothelial cell deletion of ET-1 (VEET KO), would improve recovery of renal perfusion and repair of injury following a severe ischemic insult in mice (45 min unilateral renal ischemia). Male C57Bl/6 mice receiving vehicle or ABT-627 commencing 2 days prior to surgery, and VEET KO mice and wild-type littermates (WT) underwent 45 min unilateral renal IR surgery followed by 28 days recovery. Renal blood velocity was measured by pulsed-wave Doppler ultrasound before and after surgery. Renal blood velocity was not significantly different between pairs of groups before surgery. Unilateral IR induced a marked reduction in renal blood velocity of the IR kidney at 24 h postsurgery in all groups, which partially recovered but remained below baseline at 28 days post-IR. Despite the lack of effect on renal blood velocity, ETAreceptor blockade significantly attenuated the atrophy of the post-IR kidney, whereas this was not significantly affected by lack of endothelial ET-1 expression. These data suggest that although blockade of the ETAreceptor is mildly beneficial in preserving renal mass following a severe ischemic insult, this protective effect does not appear to involve improved recovery of renal perfusion.
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska erika.boesen@unmc.edu.
authors.forename: Erika I
authors.initials: EI
authors.lastname: Boesen
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000601:surgery; D000818:Animals; D000077868:Atrasentan; D001783:Blood Flow Velocity / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000235:genetics* / Q000502:physiology*; D007511:Ischemia; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011759:Pyrrolidines / Q000494:pharmacology; D051436:Renal Insufficiency, Chronic / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D018617:Ultrasonography, Doppler, Pulsed / Q000379:methods; D015854:Up-Regulation / Q000235:genetics
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D000077868:Atrasentan
keywords: Endothelin‐1; ischemia; kidney; renal perfusion; ultrasound