GLOMERULAR EPITHELIAL CELL METABOLISM IN DIABETES MELLIT

糖尿病的肾小球上皮细胞代谢

• 批准号: 3242299
• 负责人: BALAKUNTALAM S KASINATH
• 金额: $ 12.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3242299
• 关键词: L iditol dehydrogenase; diabetic nephropathy; epithelium; glucose metabolism; heparan sulfate; insulin; kidney metabolism; laboratory rat; medical complication; proteoglycan; renal glomerulus; sialate; surface property; tissue /cell culture

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.

糖尿病肾病的特征是显著的肾脏紊乱。 肾小球基底膜的生化成分。肝素 硫酸盐蛋白多糖、唾液酸。尽管这些异常现象 与蛋白尿的发病机制有关的潜在机制 都是未知的。糖尿病并发症发病机制的研究进展 影响其他组织，例如。晶状体，周围神经，提示了一种 葡萄糖的醇衍生物，即山梨醇、肌醇- 肌醇(多元醇)。纠正多元醇中异常情况的药物 这些组织中的新陈代谢已被证明逆转了它们的功能 骚乱。我们已经成功地培育出了克隆的纯种群 肾小球上皮细胞在体外表达的特性 这些细胞在体内，例如。硫酸乙酰肝素、唾液酸、 胶原蛋白。我们建议检验这样一种假设，即 肾小球上皮细胞多元醇代谢是肾小球疾病的主要原因 肾小球HSPG代谢紊乱和唾液酸含量 糖尿病肾小球病变。我们的具体目标是： I.确定改变培养液中葡萄糖浓度的影响 和胰岛素对核心蛋白合成和分解代谢速率的影响 硫酸乙酰肝素蛋白多糖的糖胺多聚糖。 二、对所涉机制的评价：评估纠正 胰岛素缺乏，预防或逆转山梨醇和 肌醇纠正肌醇合成和分解代谢的变化 硫酸乙酰肝素蛋白多糖。 三、(A)研究改变葡萄糖浓度的影响 胰岛素对肾小球上皮细胞唾液酸含量的影响 以及电池的整个表面上的电荷。(B)至 研究纠正(I)胰岛素缺乏(Ii)异常是否 山梨醇和肌醇纠正唾液酸含量和 表面电荷异常。 这些研究将促进我们对潜在机制的理解 血液生化决定因素代谢异常的研究进展 肾小球通透性。这些知识可能为设计铺平道路 糖尿病肾病的治疗策略 发病率和死亡率。