Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: Effects of ACEI and ARB
Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: Effects of ACEI and ARB
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DOI：
10.1046/j.1523-1755.2002.00123.x
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发表时间：
2002-01-01
影响因子：
19.6
通讯作者：
Wilcox, CS
中科院分区：
文献类型：
--
作者：
Onozato, ML;Tojo, A;Wilcox, CS
背景。血管紧张素II （Ang II）可上调烟酰胺腺嘌呤二核苷酸磷酸[NAD(P)H]氧化酶，其产物超氧阴离子（O-2(-)）可与一氧化氮（NO）相互作用形成过氧亚硝酸盐（ONOO-）。我们验证了Ang II亚型1 （AT(1)）受体激活对糖尿病（DM）大鼠肾脏氧化应激和硝基酪氨酸沉积的影响。在两周的链脲佐菌素诱导糖尿病后，大鼠要么不接受治疗。血管紧张素转换酶抑制剂（ACEI）或血管紧张素受体阻滞剂（ARB）两周。第4周时，采用Western blot和免疫组织化学方法检测肾脏中NAD(P)H氧化酶、内皮型一氧化氮合酶（eNOS）、神经元型一氧化氮合酶（nNOS）和硝基酪氨酸的p47phox组分的表达，并与血浆脂质过氧化产物（LPO）相关。肾脏中过氧化氢的产生和24小时蛋白质排泄。糖尿病患者p47phox和eNOS的免疫反应性表达随着血浆LPO、肾脏过氧化氢生成和硝基酪氨酸沉积的增加而增加。nNOS的表达无明显变化。用ACEI或ARB治疗可以预防所有这些发现，也可以预防显著的微量白蛋白尿。治疗对血糖升高没有影响，糖尿病及其治疗对血压和肌酐清除率也没有影响。早期蛋白尿糖尿病肾病增加肾脏NAD(P)H氧化酶p47phox组分和eNOS的表达，并增加全身和肾脏氧化/亚硝化应激指标。ACEI或An:RB可以防止这些变化，并防止蛋白尿的发展，独立于血压或血糖。这一发现表明AT(1)受体在糖尿病早期肾脏氧化损伤发展中的致病作用。
Background. Angiotensin II (Ang II) can up-regulate nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase, whose product superoxide anion (O-2(-)) can interact with nitric oxide (NO) to form peroxynitrite (ONOO-). We tested the hypothesis that Ang II subtype 1 (AT(1)) receptor activation enhances oxidative stress an nitrotyrosine deposition in the kidneys of rats with diabetes mellitus (DM).Methods. After two weeks of streptozotocin-induced DM, rats received either no treatment. an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) for two weeks. At four weeks, renal expression of the p47phox component of NAD(P)H oxidase, endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and nitrotyrosine were evaluated by Western blot and immunohistochemistry and related to plasma lipid peroxidation products (LPO). hydrogen peroxide production in the kidney and 24-hour protein excretion.Results. Immunoreactive expression of p47phox and eNOS were increased in DM with an increase in plasma LPO, renal hydrogen peroxide production and nitrotyrosine deposition. Expression of nNOS was unaltered. Treatment with either ACEI or ARB prevented all these findings and also prevented significant microalbuminuria. The treatments did not affect the elevated blood sugar, nor did DM or its treatment affect the blood pressure or the creatinine clearance.Conclusion. Early proteinuric diabetic nephropathy increases renal expression of the p47phox component of NAD(P)H oxidase and eNOS with increased indices of systemic and renal oxidative/nitrosative stress. An ACEI or an :RB prevents these changes and prevents the development of proteinuria, independent of blood pressure or blood sugar. This finding indicates a pathogenic role for AT(1) receptors in the development of oxidative damage in the kidneys during early DM.