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Role of H 2 O 2 in hypertension, renin‐angiotensin system activation and renal medullary disfunction caused by angiotensin II
Author(s) -
Sousa T,
Oliveira S,
Afonso J,
Morato M,
Patinha D,
Fraga S,
Carvalho F,
AlbinoTeixeira A
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.01957.x
Subject(s) - endocrinology , medicine , renin–angiotensin system , angiotensin ii , renal medulla , chemistry , kidney , plasma renin activity , renal cortex , urinary system , receptor , blood pressure
BACKGROUND AND PURPOSE 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). EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.