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

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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.