Onozato Maristela Lika, Tojo Akihiro, Goto Atsuo, Fujita Toshiro, Wilcox Christopher S
Division of Nephrology and Endocrinology, University of Tokyo, Tokyo, Japan.
Kidney Int. 2002 Jan;61(1):186-94. doi: 10.1046/j.1523-1755.2002.00123.x.
Angiotensin II (Ang II) can up-regulate nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase, whose product superoxide anion (O2-) can interact with nitric oxide (NO) to form peroxynitrite (ONOO-). We tested the hypothesis that Ang II subtype 1 (AT1) receptor activation enhances oxidative stress and nitrotyrosine deposition in the kidneys of rats with diabetes mellitus (DM).
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.
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.
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 ARB prevents these changes and prevents the development of proteinuria, independent of blood pressure or blood sugar. This finding indicates a pathogenic role for AT1 receptors in the development of oxidative damage in the kidneys during early DM.
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（O2-）可与一氧化氮（NO）相互作用形成过氧亚硝酸盐（ONOO-）。我们检验了以下假设：1型血管紧张素II（AT1）受体激活会增强糖尿病（DM）大鼠肾脏中的氧化应激和硝基酪氨酸沉积。
在链脲佐菌素诱导的DM两周后，大鼠接受为期两周的无治疗、血管紧张素转换酶抑制剂（ACEI）或血管紧张素受体阻滞剂（ARB）治疗。在四周时，通过蛋白质免疫印迹法和免疫组织化学法评估NAD(P)H氧化酶的p47phox亚基、内皮型一氧化氮合酶（eNOS）、神经元型一氧化氮合酶（nNOS）的肾脏表达以及硝基酪氨酸，并将其与血浆脂质过氧化产物（LPO）、肾脏过氧化氢生成量和24小时蛋白排泄量相关联。
DM大鼠中p47phox和eNOS的免疫反应性表达增加，同时血浆LPO、肾脏过氧化氢生成量和硝基酪氨酸沉积增加。nNOS的表达未改变。ACEI或ARB治疗可防止所有这些结果，还可防止明显的微量白蛋白尿。这些治疗不影响血糖升高，DM及其治疗也不影响血压或肌酐清除率。
早期蛋白尿性糖尿病肾病会增加NAD(P)H氧化酶的p47phox亚基和eNOS的肾脏表达，同时全身和肾脏氧化/亚硝化应激指标增加。ACEI或ARB可防止这些变化并防止蛋白尿的发生，与血压或血糖无关。这一发现表明AT1受体在早期DM期间肾脏氧化损伤的发生中起致病作用。
