Role of H(2)O(2) in hypertension, renin-angiotensin system activation and renal medullary disfunction caused by angiotensin II

BACKGROUND AND PURPOSE

Activation of the intrarenal renin-angiotensin system (RAS) and increased renal medullary hydrogen peroxide (H₂O₂) contribute to hypertension. We examined whether H₂O₂ 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. H₂O₂, angiotensin AT₁ receptor and Nox4 expression and nuclear factor-κB (NF-κB) activation were evaluated in the kidney. Plasma and urinary H₂O₂ and angiotensinogen were also measured.

KEY RESULTS

Ang II increased H₂O₂, AT₁ receptor and Nox4 expression and NF-κB activation in the renal medulla, but not in the cortex. Ang II raised plasma and urinary H₂O₂ 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 AT₁ receptors and Nox4 in Ang II-infused rats. Renal medullary NF-κB activation was correlated with local H₂O₂ 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. H₂O₂ appears to be the key mediator enhancing intrarenal RAS activation and decreasing systemic RAS activity. The specific control of renal medullary H₂O₂ levels may provide future grounds for the treatment of hypertension.