title: Stabilization of hypoxia inducible factor-1α ameliorates acute renal neurogenic hypertension.
abstract: OBJECTIVE
  Renal neurogenic hypertension (RNH) contributes to cardiovascular morbidity. Renal hypoxia may cause RNH and vice versa, leading to a vicious circle. Hypoxia adaptation is conferred through hypoxia-inducible factors (HIFs). We hypothesized that acute RNH is accompanied by increased renal vascular resistance (RVR) and that hypertension and increased RVR are countered by increasing HIF-1α by cobalt chloride (CoCl2) preconditioning.
  
  
  METHODS
  First, we studied mean arterial pressure (MAP) and RVR in innervated or denervated contralateral kidneys in anesthetized rats before and after unilateral intrarenal injection of phenol, a manoeuvre known to elicit acute RNH. Then HIFα was induced by CoCl2 in drinking water (2 mM, 10 days) after which we compared intrarenal isotonic saline or phenol injection on MAP and RVR in CoCl2 preconditioned and control rats. HIF-1α was determined by immunohistochemistry.
  
  
  RESULTS
  Unilateral intrarenal phenol induced immediate rise in MAP and contralateral RVR, and comparable HIF-1α upregulation in both kidneys, consistent with bi-renal hypoxia. Removing the phenol-injected kidney immediately normalized MAP. Contralateral renal denervation had no effect on the rise in MAP, but abrogated the contralateral increase in RVR, suggesting mediation by increased efferent nerve activity. Strong renal staining for HIF-1α confirmed efficacy of CoCl2 preconditioning, and time-dependent increase in heme oxygenase-1 gene expression stabilization of HIFα. CoCl2 preconditioning prior to phenol reduced both ΔMAP (+10 ± 2 vs. +20 ± 3%, P=0.015) and ΔRVR (+21 ± 11 vs. +90 ± 26%, P=0.003).
  
  
  CONCLUSIONS
  Acute RNH leads to renal vasoconstriction and increased renal HIF-1α. Increasing HIF-1α by CoCl2 preconditioning ameliorates intrarenal phenol-induced RNH and renal vasoconstriction.
authors.affiliation: aDepartment of Nephrology and Hypertension, University Medical Center Utrecht, the Netherlands bCharité Universitaetsmedizin, Nephrology, Berlin, Germany cDivision of Pharmacology, Department of Internal Medicine, Vascular and Metabolic Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Maarten P
authors.initials: MP
authors.lastname: Koeners
authors.forename: Eva E
authors.initials: EE
authors.lastname: Vink
authors.forename: Arno
authors.initials: A
authors.lastname: Kuijper
authors.forename: Niels
authors.initials: N
authors.lastname: Gadellaa
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenberger
authors.forename: Susanne
authors.initials: S
authors.lastname: Mathia
authors.forename: Anton H
authors.initials: AH
authors.lastname: van den Meiracker
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Blankestijn
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003035:Cobalt / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D006977:Hypertension, Renal / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000502:physiology*; D007668:Kidney / Q000098:blood supply / Q000294:innervation / Q000503:physiopathology; D008297:Male; D019800:Phenol / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019800:Phenol; D003035:Cobalt; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C018021:cobaltous chloride