Langham R G, Kelly D J, Cox A J, Thomson N M, Holthöfer H, Zaoui P, Pinel N, Cordonnier D J, Gilbert R E
University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
Diabetologia. 2002 Nov;45(11):1572-6. doi: 10.1007/s00125-002-0946-y. Epub 2002 Sep 25.
AIMS/HYPOTHESIS: Proteinuria, reflecting increased glomerular permeability to macromolecules is a characteristic feature of diabetic nephropathy. Nephrin, a 1241-residue transmembrane protein is a key component of the podocyte slit pore membrane and a major contributor of the glomerular filtration barrier. We investigated the expression of nephrin in human kidney tissue from patients with diabetic nephropathy to elucidate its relationship with proteinuria and the effects of anti-proteinuric therapy with angiotensin converting enzyme inhibition.
Renal biopsies were examined from 14 patients with Type II (non-insulin-dependent) diabetes mellitus and proteinuria who had been randomised to receive treatment with the ACE inhibitor, perindopril (4 mg/day) or placebo for the preceding 2 years. These specimens were compared with control human tissue sections, obtained from areas of normal renal cortex following nephrectomy for malignancy. Proteinuria was measured, specimens were examined histologically for injury and the expression of nephrin messenger RNA was assessed by quantitative in situ hybridisation.
Glomeruli from placebo-treated patients with diabetic nephropathy, showed a 62% reduction in nephrin expression compared with control subjects (p=0.0003). In contrast, nephrin RNA in glomeruli from perindopril treated patients was similar to that in the non-diabetic control group. In both placebo and perindopril treated patients, a close inverse correlation was noted between the magnitude of nephrin gene expression and the degree of proteinuria (placebo: r=0.86, p=0.013, perindopril: r=0.91, p=0.004).
CONCLUSION/INTERPRETATION: Modulation in nephrin expression is related to the extent of proteinuria in diabetic nephropathy. These changes define, at a molecular level alterations in the glomerulus that occur in relation to proteinuria in diabetes and the effects of anti-proteinuric treatment with ACE inhibition.
目的/假设：蛋白尿反映肾小球对大分子物质通透性增加，是糖尿病肾病的一个特征性表现。Nephrin是一种含1241个氨基酸残基的跨膜蛋白，是足细胞裂孔隔膜的关键成分，也是肾小球滤过屏障的主要贡献者。我们研究了糖尿病肾病患者肾组织中Nephrin的表达，以阐明其与蛋白尿的关系以及血管紧张素转换酶抑制抗蛋白尿治疗的效果。
对14例II型（非胰岛素依赖型）糖尿病伴蛋白尿患者的肾活检标本进行检查，这些患者在之前2年被随机分配接受血管紧张素转换酶抑制剂培哚普利（4mg/天）或安慰剂治疗。将这些标本与从因恶性肿瘤行肾切除术后的正常肾皮质区域获取的对照人体组织切片进行比较。测量蛋白尿，对标本进行组织学损伤检查，并通过定量原位杂交评估Nephrin信使核糖核酸的表达。
与对照组相比，接受安慰剂治疗的糖尿病肾病患者肾小球中Nephrin表达降低了62%（p=0.0003）。相比之下，接受培哚普利治疗患者的肾小球中Nephrin RNA与非糖尿病对照组相似。在接受安慰剂和培哚普利治疗的患者中，均发现Nephrin基因表达水平与蛋白尿程度呈密切负相关（安慰剂组：r=0.86，p=0.013；培哚普利组：r=0.91，p=0.004）。
结论/解读：Nephrin表达的调节与糖尿病肾病中蛋白尿的程度有关。这些变化在分子水平上定义了糖尿病中与蛋白尿相关的肾小球改变以及血管紧张素转换酶抑制抗蛋白尿治疗的效果。
