Departamento de Farmacologia e Terapêutica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
Br J Pharmacol. 2012 Aug;166(8):2386-401. doi: 10.1111/j.1476-5381.2012.01957.x.
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).
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.
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.
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.
肾内肾素-血管紧张素系统（RAS）的激活和肾髓质过氧化氢（H₂O₂）的增加导致高血压。我们研究了 H₂O₂ 是否介导了血管紧张素 II（Ang II）引起的高血压和肾内 RAS 激活。
从第 0 天到第 14 天，向 Sprague Dawley 大鼠输注 Ang II（200ng·kg⁻¹·min⁻¹）或生理盐水。从第 7 天到第 14 天，向 Ang II 处理的大鼠给予聚乙二醇（PEG）-过氧化氢酶（10000U·kg⁻¹·天⁻¹）。整个研究过程中测量收缩压。评估肾脏中的 H₂O₂、血管紧张素 AT₁受体和 Nox4 表达以及核因子-κB（NF-κB）的激活。还测量了血浆和尿液中的 H₂O₂和血管紧张素原。
Ang II 增加了肾髓质中的 H₂O₂、AT₁受体和 Nox4 表达以及 NF-κB 的激活，但在皮质中没有。Ang II 升高了血浆和尿液中的 H₂O₂ 水平，增加了尿液中的血管紧张素原，但降低了血浆中的血管紧张素原。PEG-过氧化氢酶具有短期的降压作用，并短暂抑制了尿液中的血管紧张素原。PEG-过氧化氢酶降低了 Ang II 输注大鼠肾髓质中的 AT₁ 受体和 Nox4 表达。肾髓质 NF-κB 的激活与局部 H₂O₂ 水平和尿液中血管紧张素原的排泄有关。降压疗效的丧失与血浆血管紧张素原增加 8 倍有关。
肾髓质是 Ang II 引起的氧化还原功能障碍的主要靶点。H₂O₂ 似乎是增强肾内 RAS 激活和降低全身 RAS 活性的关键介质。肾髓质中 H₂O₂ 水平的特异性控制可能为高血压的治疗提供未来的基础。
