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

背景和目的：1994年，我们首次证实载脂蛋白（apo）E ε2等位基因与糖尿病肾病的进展相关。众所周知，载脂蛋白E2可导致残余脂蛋白的高血浆水平。为进一步探讨载脂蛋白E基因多态性、残余脂蛋白与糖尿病肾病的关系，将糖尿病病程10年以上的2型糖尿病患者分为载脂蛋白E2（n=22）、E3/3（n=102）和E4（n=34）3组。测量血脂和残余脂蛋白的血浆水平。使用载脂蛋白E2患者的肾活检标本进行组织学研究。结果：载脂蛋白E_2（apoE_2）糖尿病患者的显性肾病发生率（59.1%）明显高于载脂蛋白E_3/3（34.3%）和载脂蛋白E_4（8.8%）糖尿病患者，载脂蛋白E_3/3和E_4组的显性肾病发生率也有显著性差异。载脂蛋白E3/3患者血浆甘油三酯和残粒样脂蛋白颗粒（RLP）-胆固醇水平显著高于载脂蛋白E2患者，载脂蛋白E4患者显著低于载脂蛋白E3/3患者。对数回归分析显示，高血浆残留（RLP-C ≤ 5.2mg/dl）与存在明显肾病的比值比为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。免疫组化显示apo E2患者肾小球内apo E和apo B染色阳性。与apoE 3/3-IDL相比，ApoE 2-IDL可显著促进系膜细胞PKC活性、TGF-β合成、IV型胶原和纤维连接蛋白的合成。结论：残余脂蛋白在糖尿病肾病的发生发展中可能起重要作用。

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.