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Study on the mechanism by which apolipoprotein(apo) E2 promotes diabetic nephropathy

载脂蛋白(apo)E2促进糖尿病肾病的机制研究

基本信息

批准号：
14571112
负责人：
ETO Masaaki
金额：
$ 1.66万
依托单位：
Kawasaki Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571112/
关键词：
diabetic nephropathy apo E2 apolipoprotein apo E genotype remnant lipoproteins TGF-b mesangial cells PKC activity アポリポプロテインE 危険因子 PKC TGF-β

项目摘要

Background and Aim : In 1994 we first demonstrated that the apolipoprotein(apo) E ε2 allele is associated with the progression of diabetic nephropathy. Apo E2 is well known to contribute to high plasma levels of remnant lipoproteins. The aim of the present study is to further investigate the association between apo E genetic polymorphism, remnant lipoproteins and diabetic nephropathy.Subjects and Methods : Type 2 diabetic patients who had a diabetes duration over 10 years were divided into the 3 apo E groups ; apo E2(n=22),E3/3(n=102) and E4(n=34). Plasma levels of lipids and remnant lipoproteins were measured. Histologic studies were performed using renal biopsy specimens in apo E2 patient. The effects of apo E2-IDL(remnant lipoproteins) on cultured human mesangial cells were studied.Results : The frequency of overt nephropathy was significantly higher in apo E2 diabetic patients(59.1%) than in apo E3/3(34.3%) or apo E4 patients(8.8%), and there was also a significant difference in the frequency of overt nephropathy between apo E3/3 and E4 groups. Plasma levels of triglyceride and remnant-like lipoprotein particles(RLP)-chol and were significantly higher in apo E2 patients, and significantly lower in apo E4 patients than in apo E3/3 patients. Logistical regression analysis showed that odds ratios of high plasma remnant(RLP-C≧5.2mg/dl) for the presence of overt nephropathy were 3.614(p=0.0208). Histological renal change of apo E2 patient was almost identical to diabetic nephropathy. Immunohistochemically, apo E and apo B were stained in glomerulus of apo E2 patient. Apo E2-IDL stimulated significantly PKC activity, TGF-b synthesis, and type IV collagen and fibronectin synthesis in mesangial cells sa compared with apo E3/3-IDL.Conclusion : Remnant lipoproteins may have an important role in the progression of diabetic nephropathy.

背景与目的：1994年，我们首次证实载脂蛋白E ε2等位基因与糖尿病肾病的进展有关。众所周知，载脂蛋白E2会导致血浆中残余脂蛋白的高水平。本研究旨在进一步探讨载脂蛋白E基因多态性、残馀脂蛋白与糖尿病肾病的关系。研究对象和方法：2型糖尿病患者病程超过10年，分为3组载脂蛋白E；载脂蛋白E2(n=22),E3/3（n=102）和E4（n=34）。测定血脂和残余脂蛋白的血浆水平。采用载脂蛋白E2患者肾活检标本进行组织学研究。研究了载脂蛋白E2-IDL对培养的人系膜细胞的影响。结果：载脂蛋白E2糖尿病患者的显性肾病发生率（59.1%）明显高于载脂蛋白E3/3组（34.3%）和载脂蛋白E4组（8.8%），且载脂蛋白E3/3组和载脂蛋白E4组的显性肾病发生率也有显著性差异。apo E2患者血浆甘油三酯和残余样脂蛋白颗粒(RLP)-chol和血浆水平显著高于apo E2患者，而apo E4患者血浆水平显著低于apo E3/3患者。logistic回归分析显示，高血浆残差（RLP-C≧5.2mg/dl）与显性肾病的比值比为3.614（p=0.0208）。载脂蛋白E2患者肾脏组织学改变与糖尿病肾病基本一致。免疫组织化学方法对载脂蛋白E2患者肾小球进行载脂蛋白E、B染色。与载脂蛋白e2 /3- idl相比，载脂蛋白E2-IDL显著刺激系膜细胞PKC活性、TGF-b合成以及IV型胶原和纤维连接蛋白合成。结论：残馀脂蛋白可能在糖尿病肾病的发展过程中起重要作用。