Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats
Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats
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DOI：
10.1161/01.hyp.0000118519.66430.22
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发表时间：
2004-04-01
期刊：
影响因子：
8.3
通讯作者：
Abe, Y
中科院分区：
文献类型：
--
作者：
Nishiyama, A;Yao, L;Abe, Y
进行研究以检验活性氧 (ROS) 和丝裂原激活蛋白激酶 (MAPK) 有助于醛固酮/盐诱导的肾损伤发病机制的假设。给大鼠饮用 1% 氯化钠，并用以下组合之一治疗 6 周：媒介物（0.5% 乙醇，SC，n = 6）；醛固酮（0.75 杯/小时，SC，n = 8）；醛固酮加选择性盐皮质激素受体拮抗剂；依普利酮（食物中 0.125%，n = 8）；醛固酮加抗氧化剂；和 tempol（饮用溶液中 3 mmol/L，n = 8）。通过蛋白质印迹分析测量肾皮质组织中 MAPK 的活性，包括细胞外信号调节激酶 (ERK)1/2、c-Jun-NH2 末端激酶 (JNK)、p38MAPK 和 big-MAPK-1 (BMK1)。醛固酮输注大鼠表现出比载体输注大鼠更高的收缩压（165 +/- 5 mm Hg）和尿蛋白排泄（106 +/- 24 mg/d）（118 +/- 3 mm Hg 和 10 +/- 3 mg/d）。通过实时聚合酶链反应测量，注射醛固酮的大鼠肾皮质 p22phox、Nox-4 和 gp91phox mRNA 表达分别增加了 2.3、4.3 和 3.0 倍。醛固酮组肾皮质中硫代巴比妥酸反应物质（TBARS）的含量（0.23 +/- 0.02）也高于载体输注大鼠（0.09 +/- 0.01 nmol/mg 蛋白质）。在注射醛固酮的大鼠中，ERK1/2、JNK 和 BMK1 活性分别显着升高 3.3、2.3 和 3.0 倍，而 p38MAPK 活性没有变化。对醛固酮输注的大鼠同时给予依普利农或tempol可预防高血压的发生（127 +/- 2和125 +/- 5 mm Hg），以及蛋白质尿排泄量（10 +/- 2和9 +/- 2 mg/天）或TBARS含量（0.08 +/- 0.01和0.11 +/- 0.01 nmol/mg蛋白质）的升高。此外，依普利酮和 tempol 治疗使 ERK1/2、JNK 和 BMK1 的活性正常化。这些数据表明 ROS 和 MAPK 在醛固酮慢性升高引起的肾损伤的进展中发挥作用。
Studies were performed to test the hypothesis that reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) contribute to the pathogenesis of aldosterone/salt-induced renal injury. Rats were given 1% NaCl to drink and were treated with one of the following combinations for 6 weeks: vehicle (0.5% ethanol, SC, n = 6); aldosterone (0.75 mug/H, SC, n = 8); aldosterone plus a selective mineralocorticoid receptor antagonist; eplerenone (0.125% in chow, n = 8); aldosterone plus an antioxidant; and tempol (3 mmol/L in drinking solution, n = 8). The activities of MAPKs, including extracellular signal-regulated kinases (ERK)1/2, c-Jun-NH2-terminal kinases (JNK), p38MAPK, and big-MAPK-1 (BMK1) in renal cortical tissues were measured by Western blot analysis. Aldosterone-infused rats showed higher systolic blood pressure (165 +/- 5 mm Hg) and urinary excretion of protein (106 +/- 24 mg/d) than vehicle-infused rats (118 +/- 3 mm Hg and 10 +/- 3 mg/d). Renal cortical mRNA expression of p22phox, Nox-4, and gp91phox, measured by real-time polymerase chain reaction, was increased in aldosterone-infused rats by 2.3, 4.3, and 3.0-fold, respectively. Thiobarbituric acid-reactive substances (TBARS) content in renal cortex was also higher in aldosterone (0.23 +/- 0.02) than vehicle-infused rats (0.09 +/- 0.01 nmol/mg protein). ERK1/2, JNK, and BMK1 activities were significantly elevated in aldosterone-infused rats by 3.3, 2.3, and 3.0-fold, respectively, whereas p38MAPK activity was not changed. Concurrent administration of eplerenone or tempol to aldosterone-infused rats prevented the development of hypertension (127 +/- 2 and 125 +/- 5 mm Hg), and the elevations of urinary excretion of protein (10 +/- 2 and 9 +/- 2 mg/day) or TBARS contents (0.08 +/- 0.01 and 0.11 +/- 0.01 nmol/mg protein). Furthermore, eplerenone and tempol treatments normalized the activities of ERK1/2, JNK, and BMK1. These data suggest that ROS and MAPK play a role in the progression of renal injury induced by chronic elevations in aldosterone.