title: Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease.
abstract: Endothelin (ET)-1, a potent renal vasoconstrictor with mitogenic properties, is upregulated by ischemia and has been shown to induce renal injury via the ET-A receptor. The potential role of ET-A blockade in chronic renovascular disease (RVD) has not, to our knowledge, been previously reported. We hypothesized that chronic ET-A receptor blockade would preserve renal hemodynamics and slow the progression of injury of the stenotic kidney in experimental RVD. Renal artery stenosis, a major cause of chronic RVD, was induced in 14 pigs and observed for 6 wk. In half of the pigs, chronic ET-A blockade was initiated (RVD+ET-A, 0.75 mg·kg(-1)·day(-1)) at the onset of RVD. Single-kidney renal blood flow, glomerular filtration rate, and perfusion were quantified in vivo after 6 wk using multidetector computer tomography. Renal microvascular density was quantified ex vivo using three-dimensional microcomputer tomography, and growth factors, inflammation, apoptosis, and fibrosis were determined in renal tissue. The degree of stenosis and increase in blood pressure were similar in RVD and RVD+ET-A pigs. Renal hemodynamics, function, and microvascular density were decreased in the stenotic kidney but preserved by ET-A blockade, accompanied by increased renal expression of vascular endothelial growth factor, hepatocyte growth factor, and downstream mediators such as phosphorilated-Akt, angiopoietins, and endothelial nitric oxide synthase. ET-A blockade also reduced renal apoptosis, inflammation, and glomerulosclerosis. This study shows that ET-A blockade slows the progression of renal injury in experimental RVD and preserves renal hemodynamics, function, and microvascular density in the stenotic kidney. These results support a role for ET-1/ET-A as a potential therapeutic target in chronic RVD.
authors.affiliation: Dept. of Physiology and Biophysics, Dept. of Medicine, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Kelsen
authors.forename: John E
authors.initials: JE
authors.lastname: Hall
authors.forename: Alejandro R
authors.initials: AR
authors.lastname: Chade
mesh_terms: D000792:Angiography; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D018450:Disease Progression; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000502:physiology; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000473:pathology*; D007677:Kidney Function Tests; D012078:Renal Artery Obstruction / Q000188:drug therapy* / Q000473:pathology*; D012079:Renal Circulation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine; D014054:Tomography; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor