Amelioration of nephropathy with apoA-1 mimetic peptide in apoE-deficient mice.
Amelioration of nephropathy with apoA-1 mimetic peptide in apoE-deficient mice.
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DOI：
10.1093/ndt/gfq274
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发表时间：
2010-11
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通讯作者：
N. Vaziri;H. J. Kim;H. Moradi;Farbod Farmand;K. Navab;M. Navab;S. Hama;A. Fogelman;Y. Quiroz;B. Rodriguez-Iturbe
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作者：
N. Vaziri;H. J. Kim;H. Moradi;Farbod Farmand;K. Navab;M. Navab;S. Hama;A. Fogelman;Y. Quiroz;B. Rodriguez-Iturbe
越来越多的证据表明血脂异常可能导致肾脏疾病的发生和进展。例如，载脂蛋白E缺陷（apoE（-/-））小鼠的脂蛋白血症与肾小球炎症、系膜扩张和泡沫细胞形成有关。ApoA-1模拟肽是一种有效的抗氧化和抗炎化合物，在改善实验动物动脉粥样硬化和炎症方面非常有效。鉴于氧化应激和炎症在肾脏疾病进展中的核心作用，我们假设apoA-1模拟肽D-4F可能减轻apoE（-/-）小鼠的肾脏病变。方法25月龄雌性apoE（-/-）小鼠分别给予D-4F（300 μg/mL饮水）或安慰剂6周。收获肾脏并检查组织学和生化特征。结果与对照组相比，apoE（-/-）小鼠出现明显的蛋白尿、肾小管间质炎症、系膜扩张、泡沫细胞形成以及氧化[NAD（P）H氧化酶亚基]和炎症[NF-κB、MCP-1、派-1和考克斯-2]途径的上调。D-4F给药降低了蛋白尿，改善了肾组织学，逆转了炎症和氧化途径的上调，血浆脂质水平仅发生轻微变化。结论apoE（-/-）小鼠出现蛋白尿、肾小球和肾小管间质损伤，这些损伤与肾脏氧化和炎症介质的上调有关，apoA-1模拟肽可减轻这些损伤。这些观察结果指出了氧化应激和炎症在肾功能不全动物（可能还有人类）肾脏疾病发病机制中的作用。
BACKGROUND There is mounting evidence that dyslipidaemia may contribute to development and progression of renal disease. For instance, hyperlipidaemia in apolipoprotein E-deficient (apoE(-/-)) mice is associated with glomerular inflammation, mesangial expansion and foam cell formation. ApoA-1 mimetic peptides are potent antioxidant and anti-inflammatory compounds which are highly effective in ameliorating atherosclerosis and inflammation in experimental animals. Given the central role of oxidative stress and inflammation in progression of renal disease, we hypothesized that apoA-1 mimetic peptide, D-4F, may attenuate renal lesions in apoE(-/-) mice. METHODS Twenty-five-month-old female apoE(-/-) mice were treated with D-4F (300 µg/mL in drinking water) or placebo for 6 weeks. Kidneys were harvested and examined for histological and biochemical characteristics. RESULTS Compared with the control mice, apoE(-/-) mice showed significant proteinuria, tubulo-interstitial inflammation, mesangial expansion, foam cell formation and up-regulation of oxidative [NAD(P)H oxidase subunits] and inflammatory [NF-κB, MCP-1, PAI-1 and COX-2] pathways. D-4F administration lowered proteinuria, improved renal histology and reversed up-regulation of inflammatory and oxidative pathways with only minimal changes in plasma lipid levels. CONCLUSIONS The apoE(-/-) mice develop proteinuria and glomerular and tubulo-interstitial injury which are associated with up-regulation of oxidative and inflammatory mediators in the kidney and are ameliorated by the administration of apoA-1 mimetic peptide. These observations point to the role of oxidative stress and inflammation in the pathogenesis of renal disease in hyperlipidaemic animals and perhaps humans.