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.

糖尿病肾病的特点是肾功能明显紊乱 肾小球基底膜的生化成分，例如。乙酰肝素 硫酸蛋白多糖、唾液酸。 尽管这些异常现象 参与蛋白尿的发病机制、潜在机制 不知道。 糖尿病并发症发病机制的研究 影响其他组织，例如。晶状体，周围神经，建议 葡萄糖的醇衍生物（即山梨醇）的重要作用 肌醇（多元醇）。 纠正多元醇异常的试剂 这些组织中的新陈代谢已被证明可以逆转其功能 干扰。 我们已经成功培育出纯克隆群体 肾小球上皮细胞在体外表达以下特征 这些细胞在体内，例如。硫酸乙酰肝素、唾液酸的表达， 胶原。 我们建议检验以下假设： 肾小球上皮细胞多元醇代谢负责 肾小球 HSPG 代谢和唾液酸含量紊乱 糖尿病肾小球病。 我们的具体目标是： I. 确定改变培养基葡萄糖浓度的影响 和胰岛素对核心蛋白合成和分解代谢速率的影响 硫酸乙酰肝素蛋白聚糖的糖胺聚糖部分。 二. 评估所涉及的机制：评估是否纠正 胰岛素缺乏，预防或逆转山梨醇异常 肌醇纠正合成和分解代谢中发现的变化 硫酸乙酰肝素蛋白多糖。 三． (a) 研究改变培养基葡萄糖浓度的影响 和胰岛素对肾小球上皮细胞唾液酸含量的影响 以及细胞的整体细胞表面电荷。 (b) 至 调查是否纠正（i）胰岛素缺乏（ii）异常 山梨醇和肌醇可纠正唾液酸含量的变化， 表面电荷异常。 这些研究将增进我们对潜在机制的理解 生化决定因素代谢异常 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会造成巨大的 发病率和死亡率。