Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy
Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy
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DOI：
10.1046/j.1523-1755.2001.00788.x
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发表时间：
2001-07-01
影响因子：
19.6
通讯作者：
Demaine, AG
中科院分区：
文献类型：
--
作者：
Hodgkinson, AD;Sondergaard, KL;Demaine, AG
背景尽管代谢控制良好，但许多1型糖尿病患者仍会发生肾病，这与遗传因素有关。最近的研究检查的醛糖还原酶（ALR 2）基因，多元醇途径的限速酶的调控区域，支持其作为一个候选基因的肾病的作用。在这里，我们报告ALR 2的定量。与山梨糖醇脱氢酶mRNA一起在1型糖尿病患者（N = 29）和无肾病患者（N = 11）的外周血单个核细胞（PBMC）中在高水平D-葡萄糖刺激后。将患者和正常对照的PBMC与植物血凝素在正常血糖（11 mmol/L D-葡萄糖）或补充有10 mmol/L D-葡萄糖（中度高血糖）或20 mmol/L D-葡萄糖（高血糖）的培养基中培养5天。提取RNA，用核糖核酸酶保护法进行分析。肾病组ALR 2 mRNA表达水平随D-葡萄糖浓度的升高而显著升高（P < 0.0001）。与此形成鲜明对比的是，在那些没有肾病的人和正常健康对照组中。mRNA表达无变化。肾脏病组和Z-2/X易感基因型患者ALR 2 mRNA表达水平较低危基因型患者显著增高（P <0. 007）。这些结果表明，肾病患者在多元醇途径的酶组分的表达中表现出明显的紊乱。最终，这导致组织损伤和局部缺血。
Background. Despite good metabolic control, many patients with type 1 diabetes still develop nephropathy, implicating a role for genetic factors. Recent studies examining the regulatory region of the aldose reductase (ALR2) gene, the rate-limiting enzyme of the polyol pathway, support its role as a candidate gene for nephropathy. Here we report the quantitation of ALR2. together with sorbitol dehydrogenase mRNA in the peripheral blood mononuclear cells (PBMCs) of type 1 diabetic patients with (N = 29) and without nephropathy (N = 11) following stimulation with high levels of D-glucose.Methods. PBMCs from patients and normal controls were cultured for five days with phytohemagglutinin in either normoglycemia (11 mmol/L D-glucose) or supplemented with 10 mmol/L D-glucose (moderate hyperglyemia) or 20 mmol/L D-glucose (hyperglycemia). The RNA was extracted and analyzed by ribonuclease protection assay.Results. ALR2 mRNA levels were significantly elevated with increasing D-glucose concentration (normal to hyperglycemic) in those patients with nephropathy (P < 0.0001). In marked contrast, in those without nephropathy and in the normal healthy controls. there was no change in mRNA expression. Furthermore, those patients with nephropathy and the Z-2/X susceptibility genotype had the greatest increase in ALR2 mRNA compared with those with low-risk genotypes (P < 0.007).Conclusion. These results show that patients with nephropathy exhibit marked disturbances in the expression of the enzyme components of the polyol pathway. Ultimately this leads to tissue damage and ischemia.