GLOMERULAR EPITHELIAL CELL METABOLISM IN DIABETES

糖尿病肾病的特征是在肾脏中的 肾小球基底膜的生化成分，如乙酰肝素 硫酸化蛋白聚糖、唾液酸。 虽然这些异常是 与蛋白尿的发病机制有关， 不知道。 糖尿病并发症的发病机制研究 影响其他组织，透镜，周围神经，都表明 葡萄糖的醇衍生物，即山梨糖醇，肌 肌醇（多元醇）。 纠正多元醇异常的试剂 这些组织中的代谢已经显示出逆转它们的功能 干扰. 我们已经成功地培育出了 肾小球上皮细胞，在体外表达的特点， 这些细胞在体内例如硫酸乙酰肝素，唾液酸， 胶原 我们建议测试的假设，在异常的 肾小球上皮细胞多元醇代谢负责 肾小球HSPG代谢和唾液酸含量的紊乱， 糖尿病性肾小球病 我们的具体目标是： I. 为了确定改变培养基中葡萄糖浓度的影响， 和胰岛素对核心蛋白的合成和催化速率的影响， 硫酸乙酰肝素蛋白聚糖的糖胺聚糖部分。 二. 评估所涉机制： 胰岛素缺乏，预防或逆转山梨醇异常， 肌醇纠正在合成和催化中发现的变化， 硫酸乙酰肝素蛋白聚糖。 三. (a)研究改变培养基中葡萄糖浓度的影响 胰岛素对肾小球上皮细胞唾液酸含量的影响 以及电池的整个电池表面电荷。 (b)到 研究是否纠正（i）胰岛素缺乏（ii） 山梨糖醇和肌醇纠正唾液酸含量变化， 表面电荷异常。 这些研究将促进我们对潜在机制的理解 在代谢的生化决定因素的异常， 肾小球选择透过性 这些知识可以为设计 糖尿病肾病的治疗策略， 发病率和死亡率。

Diabetic nephropathy is characterized by significant derangements in the biochemical constituents of the glomerular basement membrane eg. heparan sulfate proteoglycan, sialic acid. Although these abnormalities are implicated in the pathogenesis of proteinuria, the underlying mechanisms are not known. Studies on pathogenesis of diabetic complications affecting other tissues eg. lens, peripheral nerves, have suggested an important role for alcohol derivatives of glucose i.e. sorbitol, myo- inositol (polyols). Agents that correct the abnormalities in polyol metabolism in these tissues have been shown to reverse their functional disturbances. We have successfully grown pure populations of cloned glomerular epithelial cells which express in vitro the characteristics of these cells in vivo eg. expression of heparan sulfate, sialic acid, collagen. We propose to test the hypothesis that abnormalities in the glomerular epithelial cell polyol metabolism are responsible for the derangements in glomerular HSPG metabolism and sialic acid content seen in diabetic glomerulopathy. Our specific aims are: I. To determine the effect of altered medium concentrations of glucose and insulin on the rates of synthesis and catabolism of core protein and glycosaminoglycan moieties of heparan sulfate proteoglycan. II. Evaluation of mechanisms involved: To assess whether correcting insulin lack, preventing or reversing abnormalities in sorbitol and myoinositol rectify changes found in the synthesis and catabolism of heparan sulfate proteoglycan. III. (a) To study the effects of altered medium concentrations of glucose and insulin on the sialic acid content of the glomerular epithelia cells and on the overall cell surface electrical charge of the cells. (b) To investigate whether correcting (i) insulin lack (ii) abnormalities in sorbitol and myo-inositol rectify changes in sialic acid content and abnormalities in surface electrical charge. These studies will advance our understanding of the mechanisms underlying the abnormalities in the metabolism of biochemical determinants of glomerular permselectivity. This knowledge may pave way to design therapeutic strategies for diabetic nephropathy that causes enormous morbidity and mortality.