The SOD mimetic tempol ameliorates glomerular injury and reduces mitogen-activated protein kinase activity in Dahl salt-sensitive rats
The SOD mimetic tempol ameliorates glomerular injury and reduces mitogen-activated protein kinase activity in Dahl salt-sensitive rats
复制标题
DOI：
10.1097/01.asn.0000108523.02100.e0
复制
发表时间：
2004-02-01
影响因子：
13.6
通讯作者：
Abe, Y
中科院分区：
文献类型：
--
作者：
Nishiyama, A;Yoshizumi, M;Abe, Y
近年来研究表明，Dahl盐敏感性高血压大鼠肾损伤伴随有丝裂原活化蛋白激酶（MAPK）的激活。本研究旨在阐明活性氧在DS大鼠MAPK活性和肾损伤中的作用。DS大鼠维持高盐（H; 8.0%NaCl; n = 7）或低盐（L; 0.3%NaCl; n = 6）饮食; H +超氧化物歧化酶模拟物Tempol（3 mmol/L饮用水; n = 8）;或H +肼苯哒嗪（0.5mmol/L饮用水; n = 8）4周。DS/H和DS/L大鼠的平均BP（MBP）分别为185 +/- 7和113 +/- 3 mmHg。与DS/L大鼠相比，DS/H大鼠的尿蛋白排泄和肌酐比值（U蛋白V/UcrV; 20.3 +/- 1.1）和皮质胶原含量（22 +/- 1 mug/mg）更高（分别为2.4 +/- 0.1和13 +/- 1 mug/mg）。在DS/H大鼠肾皮质组织中，NAD（P）H氧化酶的基本组分p22-phox和Nox-1的表达比DS/L大鼠高约3倍。在DS/H大鼠中还观察到肾皮质MAPK活性增加，包括细胞外信号调节激酶（ERK）1/ERK 2和c-Jun NH 2-末端激酶（JNK），分别为7.0 +/- 0.7倍和4.3 +/- 0.2倍。Tempol治疗显著降低了DS/H大鼠的MBP（128 3 mmHg）、U蛋白V/UcrV（4.8 +/- 0.4）和皮质胶原含量（14 +/- 1 μ g/mg），并使ERK 1/ERK 2和JNK活性正常化。在组织学上，tempol显著改善DS/H大鼠进行性肾小球硬化和增生性改变。肼屈嗪处理的DS/H大鼠显示出与tempo处理的DS/H大鼠相似的MBP（127 +/- 5 mmHg）。肼苯哒嗪还降低了DS/H大鼠的U蛋白V/UcrV（16.2 +/- 1.5）和皮质胶原含量（19 +/- 1 μ g/mg）。然而，这些值显著高于tempo处理的大鼠。此外，虽然肼苯哒嗪显著降低JNK活性（-56 +/-3%），但ERK 1/ERK 2活性不受影响。这些数据表明，活性氧自由基，产生的NAD（P）H氧化酶，有助于通过ERK 1/ERK 2激活在DS/H高血压大鼠肾损伤的进展。
It was shown recently that renal injury in Dahl salt-sensitive (DS) hypertensive rats is accompanied by mitogen-activated protein kinase (MAPK) activation. The present study was conducted to elucidate the contribution of reactive oxygen species to MAPK activities and renal injury in DS rats. DS rats were maintained on high salt (H; 8.0% NaCl; n = 7) or low salt (L; 0.3% NaCl; n = 6) diets; H + a superoxide dismutase mimetic, tempol (3 mmol/L in drinking water; n = 8); or H + hydralazine (0.5 mmol/L in drinking water; n = 8) for 4 wk. Mean BP (MBP) in DS/H and DS/L rats was 185 +/- 7 and 113 +/- 3 mmHg, respectively. DS/H rats showed a higher ratio of urinary protein excretion and creatinine (UproteinV/UcrV; 20.3 +/- 1.1) and a higher cortical collagen content (22 +/- 1 mug/mg) than in DS/L rats (2.4 +/- 0.1 and 13 +/- 1 mug/mg, respectively). The expression of p22-phox and Nox-1, essential components of NAD(P)H oxidase, in renal cortical tissue was approximately threefold higher in DS/H rats than in DS/L rats. Increased activities of renal cortical MAPK, including extracellular signal-regulated kinases (ERK) 1/ERK2 and c-Jun NH2-terminal kinases (JNK) were also observed in DS/H rats by 7.0 +/- 0.7- and 4.3 +/- 0.2-fold, respectively. Tempol treatment significantly decreased MBP (128 3 mmHg), UproteinV/UcrV (4.8 +/- 0.4), and cortical collagen content (14 +/- 1 mug/mg) and normalized ERK1/ERK2 and JNK activities in DS/H rats. Histologically, tempol markedly ameliorated progressive sclerotic and proliferative glomerular changes in DS/H rats. Hydralazine-treated DS/H rats showed similar MBP (127 +/- 5 mmHg) to tempol-treated DS/H rats. Hydralazine also decreased UproteinV/UcrV (16.2 +/- 1.5) and cortical collagen content (19 +/- 1 mug/mg) in DS/H rats. However, these values were significantly higher than those of tempol-treated rats. Furthermore, although hydralazine significantly reduced JNK activity (-56 +/- 3%), ERK1/ERK2 activities were unaffected. These data suggest that reactive oxygen species, generated by NAD(P)H oxidase, contribute to the progression of renal injury through ERK1/ERK2 activation in DS/H hypertensive rats.