title: Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow.
abstract: Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary. We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats. This method provides stable and continuous measurements of cortical tissue oxygen tension (PO2) for more than 2 weeks and can reproducibly detect acute changes in cortical oxygenation. Exogenous angiotensin-II reduced renal cortical tissue PO2 more than equi-pressor doses of phenylephrine, probably because it reduced renal oxygen delivery more than did phenylephrine. Activation of the endogenous renin-angiotensin system in transgenic Cyp1a1Ren2 rats reduced cortical tissue PO2; in this model renal hypoxia precedes the development of structural pathology and can be reversed acutely by an angiotensin-II receptor type 1 antagonist. Angiotensin-II promotes renal hypoxia, which may in turn contribute to its pathological effects during development of chronic kidney disease.
  
  
  
  We hypothesised that both exogenous and endogenous angiotensin-II (AngII) can decrease the partial pressure of oxygen (PO2) in the renal cortex of unrestrained rats, which might in turn contribute to the progression of chronic kidney disease. Rats were instrumented with telemeters equipped with a carbon paste electrode for continuous measurement of renal cortical tissue PO2. The method reproducibly detected acute changes in cortical oxygenation induced by systemic hyperoxia and hypoxia. In conscious rats, renal cortical PO2 was dose-dependently reduced by intravenous AngII. Reductions in PO2 were significantly greater than those induced by equi-pressor doses of phenylephrine. In anaesthetised rats, renal oxygen consumption was not affected, and filtration fraction was increased only in the AngII infused animals. Oxygen delivery decreased by 50% after infusion of AngII and renal blood flow (RBF) fell by 3.3 ml min-1. Equi-pressor infusion of phenylephrine did not significantly reduce RBF or renal oxygen delivery. Activation of the endogenous renin-angiotensin system in Cyp1a1Ren2 transgenic rats reduced cortical tissue PO2. This could be reversed within minutes by pharmacological angiotensin-II receptor type 1 (AT1R) blockade. Thus AngII is an important modulator of renal cortical oxygenation via AT1receptors. AngII had a greater influence on cortical oxygenation than did phenylephrine. This phenomenon appears to be attributable to the profound impact of AngII on renal oxygen delivery. We conclude that the ability of AngII to promote renal cortical hypoxia may contribute to its influence on initiation and progression of chronic kidney disease.
authors.affiliation: Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, The Netherlands.|Internal Medicine-Nephrology, Academic Medical Centre at the University of Amsterdam, The Netherlands.
authors.forename: Tonja W
authors.initials: TW
authors.lastname: Emans
authors.affiliation: Department of Pharmacology and Toxicology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Janssen
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.
authors.forename: Maximilian I
authors.initials: MI
authors.lastname: Pinkham
authors.affiliation: Cardiovascular Disease Program, Biosciences Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia.
authors.forename: Connie P C
authors.initials: CP
authors.lastname: Ow
authors.affiliation: Cardiovascular Disease Program, Biosciences Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Evans
authors.affiliation: Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.affiliation: Department of Physiology, University of Auckland, Auckland, New Zealand.|Millar Inc, Auckland, New Zealand.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Malpas
authors.affiliation: Internal Medicine-Nephrology, Academic Medical Centre at the University of Amsterdam, The Netherlands.
authors.forename: C T Paul
authors.initials: CT
authors.lastname: Krediet
authors.affiliation: School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK. m.koeners@bristol.ac.uk.
authors.forename: Maarten P
authors.initials: MP
authors.lastname: Koeners
mesh_terms: D000804:Angiotensin II / Q000097:blood*; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D003243:Consciousness; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008297:Male; D010101:Oxygen Consumption; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; C535029:Ren2 protein, rat; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D019363:Cytochrome P-450 CYP1A1; D012083:Renin
keywords: Cyp1a1Ren2 transgenic rat; angiotensin-II; cortex; hypoxia; kidney; oxygenation; phenylephrine; telemetry