title: Disparate effects of single endothelin-A and -B receptor blocker therapy on the progression of renal injury in advanced renovascular disease.
abstract: We hypothesized that chronic specific endothelin-A (ET-A) receptor blockade therapy would reverse renal dysfunction and injury in advanced experimental renovascular disease. To test this, unilateral renovascular disease was induced in 19 pigs, and after 6 weeks, single-kidney hemodynamics and function was quantified in vivo using computed tomography. All pigs with renovascular disease were divided such that seven were untreated, seven were treated with ET-A blockers, and five were treated with ET-B blockers. Four weeks later, all pigs were restudied in vivo, and then killed and ex vivo studies performed on the stenotic kidney to quantify microvascular density, remodeling, renal oxidative stress, inflammation, and fibrosis. Renal blood flow, glomerular filtration rate, and redox status were significantly improved in the stenotic kidney after ET-A but not ET-B blockade. Furthermore, only ET-A blockade therapy reversed renal microvascular rarefaction and diminished remodeling, which was accompanied by a marked decreased in renal inflammatory and fibrogenic activity. Thus, ET-A but not ET-B blockade ameliorated renal injury in pigs with advanced renovascular disease by stimulating microvascular proliferation and decreasing the progression of microvascular remodeling, renal inflammation, and fibrosis in the stenotic kidney. These effects were functionally consequential as ET-A blockade improved single kidney microvascular endothelial function, renal blood flow, and glomerular filtration rate, and decreased albuminuria.
authors.affiliation: 1] Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA [2] Department of Medicine, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi, USA [3] Department of Radiology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Alejandro R
authors.initials: AR
authors.lastname: Chade
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Stewart
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Peavy
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000097:blood; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D055806:Microvessels / Q000187:drug effects; D061330:Multidetector Computed Tomography; D012078:Renal Artery Obstruction / Q000188:drug therapy* / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects*; D013552:Swine
chemical_list: D015415:Biomarkers; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1