Renoprotective antioxidant effect of alagebrium in experimental diabetes.
Renoprotective antioxidant effect of alagebrium in experimental diabetes.
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DOI：
10.1093/ndt/gfr152
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发表时间：
2011-11
期刊：
影响因子：
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通讯作者：
Jehyun Park;M. Kwon;J. Huh;W. J. Choi;L. Jeong;R. Nagai;W. Kim;Jin Kim;G. Lee;Hi-Bahl Lee
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文献类型：
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作者：
Jehyun Park;M. Kwon;J. Huh;W. J. Choi;L. Jeong;R. Nagai;W. Kim;Jin Kim;G. Lee;Hi-Bahl Lee
背景：尽管阿罗格列酮（ALA）是一种公认的晚期糖基化终产物（AGE）破坏剂，对糖尿病肾病有有益作用，但其肾脏保护机制尚不完全清楚。由于氧化应激通过与AGE相互作用而加重糖尿病肾损伤，因此本研究在db/db小鼠、高糖或H2 O2培养的系膜细胞和试管中检测ALA的抗氧化特性。方法8周龄db/m和db/db小鼠（D（ALA）E）腹腔注射ALA（2 mg/kg/d）12周，16周龄db/db小鼠（D（ALA）L）腹腔注射ALA 4周。测定氧化应激标志物（硝基酪氨酸蓄积、烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基的表达和易位、细胞DCF-DA荧光）以及尿白蛋白排泄和组织学变化（包括系膜扩张）。在存在和不存在ALA的情况下，通过在试管中的碘量分析来测量H（2）O（2）的浓度。结果ALA能显著降低db/db小鼠尿白蛋白排泄量和肾脏病理改变，并能降低戊糖苷和硝基酪氨酸的蓄积和NADPH氧化酶亚基的表达。在肾小球系膜细胞中，ALA不仅能有效地阻止高糖诱导的NADPH氧化酶亚基（p47 phox，p67 phox和rac 1）和蛋白激酶C亚型（α，βI和βII）的膜转位，而且能有效地阻止H2 O2诱导的Nox 4信使RNA表达及细胞活性氧的产生。此外，ALA直接降低了试管中的H（2）O（2）。结论ALA具有直接和间接的抗氧化作用，其抗氧化作用可能是ALA保护糖尿病肾脏的重要机制之一。
BACKGROUND Despite the beneficial effects of alagebrium (ALA), a putative advanced glycation end-product (AGE) breaker, on diabetic nephropathy, its renoprotective mechanisms are incompletely understood. Since oxidative stress exacerbates diabetic renal injury through interaction with AGE, the present study examined the antioxidative property of ALA in db/db mice, mesangial cells cultured under high glucose or H(2)O(2) and a test tube. METHODS ALA (2 mg/kg/day) was administered intraperitoneally for 12 weeks to 8-week-old db/m and db/db (D(ALA)E) mice or for 4 weeks to 16-week-old db/db mice (D(ALA)L). Oxidative stress markers (nitrotyrosine accumulation, expression and translocation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, cellular DCF-DA fluorescence) together with urinary albumin excretion and histological changes including mesangial expansion were measured. The concentration of H(2)O(2) in the presence and absence of ALA was measured by iodometric analysis in a test tube. RESULTS ALA significantly reduced not only urinary albumin excretion and renal pathological changes but also accumulation of pentosidine and nitrotyrosine and expression of NADPH oxidase subunits in db/db mice regardless of treatment protocol. In mesangial cells, ALA effectively prevented not only high glucose- but also H(2)O(2)-induced membrane translocation of NADPH oxidase subunit (p47 phox, p67 phox and rac1) and protein kinase C isoform (α, βI and βII) and Nox4 messenger RNA expression concomitant with cellular reactive oxygen species. Furthermore, ALA directly decreased H(2)O(2) in a test tube. CONCLUSION ALA has both direct and indirect antioxidant effects that may play important roles in ALA's renoprotective effect in diabetic kidneys.