title: Role of H(2)O(2) in hypertension, renin-angiotensin system activation and renal medullary disfunction caused by angiotensin II.
abstract: OBJECTIVE
  Activation of the intrarenal renin-angiotensin system (RAS) and increased renal medullary hydrogen peroxide (H(2) O(2) ) contribute to hypertension. We examined whether H(2) O(2) mediated hypertension and intrarenal RAS activation induced by angiotensin II (Ang II).
  
  
  METHODS
  Ang II (200 ng·kg(-1) ·min(-1) ) or saline were infused in Sprague Dawley rats from day 0 to day 14. Polyethylene glycol (PEG)-catalase (10 000 U·kg(-1) ·day(-1) ) was given to Ang II-treated rats, from day 7 to day 14. Systolic blood pressure was measured throughout the study. H(2) O(2) , angiotensin AT(1) receptor and Nox4 expression and nuclear factor-κB (NF-κB) activation were evaluated in the kidney. Plasma and urinary H(2) O(2) and angiotensinogen were also measured.
  
  
  RESULTS
  Ang II increased H(2) O(2) , AT(1) receptor and Nox4 expression and NF-κB activation in the renal medulla, but not in the cortex. Ang II raised plasma and urinary H(2) O(2) levels, increased urinary angiotensinogen but reduced plasma angiotensinogen. PEG-catalase had a short-term antihypertensive effect and transiently suppressed urinary angiotensinogen. PEG-catalase decreased renal medullary expression of AT(1) receptors and Nox4 in Ang II-infused rats. Renal medullary NF-κB activation was correlated with local H(2) O(2) levels and urinary angiotensinogen excretion. Loss of antihypertensive efficacy was associated with an eightfold increase of plasma angiotensinogen.
  
  
  CONCLUSIONS
  The renal medulla is a major target for Ang II-induced redox dysfunction. H(2) O(2) appears to be the key mediator enhancing intrarenal RAS activation and decreasing systemic RAS activity. The specific control of renal medullary H(2) O(2) levels may provide future grounds for the treatment of hypertension.
authors.affiliation: Departamento de Farmacologia e Terapêutica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal. tsousa@med.up.pt
authors.forename: T
authors.initials: T
authors.lastname: Sousa
authors.forename: S
authors.initials: S
authors.lastname: Oliveira
authors.forename: J
authors.initials: J
authors.lastname: Afonso
authors.forename: M
authors.initials: M
authors.lastname: Morato
authors.forename: D
authors.initials: D
authors.lastname: Patinha
authors.forename: S
authors.initials: S
authors.lastname: Fraga
authors.forename: F
authors.initials: F
authors.lastname: Carvalho
authors.forename: A
authors.initials: A
authors.lastname: Albino-Teixeira
mesh_terms: D000804:Angiotensin II / Q000633:toxicity*; D000808:Angiotensinogen; D000818:Animals; D015415:Biomarkers; D002374:Catalase / Q000494:pharmacology; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced*; D007679:Kidney Medulla / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology
chemical_list: D015415:Biomarkers; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; C070295:catalase-polyethylene glycol; D000808:Angiotensinogen; D000804:Angiotensin II; D011092:Polyethylene Glycols; D006861:Hydrogen Peroxide; D002374:Catalase; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat