NONENZYMATIC GLYCOSYLATION OF THE MESANGIUM IN DIABETES

糖尿病中系膜的非酶糖基化

• 批准号: 3242370
• 负责人: Detlef Olaf Schlondorff
• 金额: $ 17.57万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1992-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3242370
• 关键词: albumins; binding proteins; cell growth regulation; cellular pathology; cytokine; diabetes mellitus; diabetic nephropathy; eicosanoids; extracellular matrix; extracellular matrix proteins; glycosylation; human subject; immunoglobulin G; laboratory rat; low density lipoprotein; membrane; mesangium; protein biosynthesis; proteolysis; renal glomerulus; tissue /cell culture; transport proteins

Diabetic nephropathy is a major cause of end-stage renal disease. In the present proposal we shall consider the potential contribution of non-enzymatic glycosylation to the pathogenesis of diabetic glomerulosclerosis, of which expansion of the mesangium is a hallmark. The study of cultured mesangial cells have already contributed considerably to our understanding of glomerular function. The mesangial cell not only responds to vasoactive agents but also generates prostaglandins, PAF, cytokines and matrix components. Mesangial cells are also capable of specific endocytosis of macromolecules. Our present knowledge on nonenzymatic glycosylation of proteins in DM and of the multiple functions of glomerular mesangial cells provide a clear rationale for the proposed studies. the use of the cultured mesangial cells and defined proteins allows experimental dissection of individual factors, an approach that could not be taken in vivo. The central hypothesis to be tested is: Formation of advanced nonenzymatic glycosylation products of mesangial matrix proteins and excessive glycosylatin of circulating plasma proteins effect mesangial cell function resulting in pathological expansion of the mesangium in the diabetic kidney. In order to test this hypothesis, we will examine the following specific questions on cultured rat mesangial cells: 1) Does non-enzymatic glycosylation alter the binding and uptake of proteins such as albumin, IgG, and low density lipoprotein by mesangial cells? 2) Does nonenzymatic glycosylation (as per question 1) alter the expression of autacoids and cytokines by mesangial cells and influence the generation of matrix? 3) Does advanced glycosylation of mesangial matrix alter its digestion by mesangial proteases? 4) Does advanced glycosylation of mesangial matrix influence cell proliferation, expression of cytokines and matrix components? The answer to these questions should provide insight into the consequences of nonenzymatic glycosylation of proteins on their mesangial accumulation, on generation of mesangial matrix and collagen, and thus eventually on diabetic glomerulosclerosis. This should allow identification of potentially pathogenetic steps, that may eventually help to design well targeted therapeutic intervention.

糖尿病性肾病是终末期肾脏疾病的主要原因。 在 目前的提议我们将考虑 非酶糖基化糖尿病发病机理 肾小球硬化，其中肾小球的扩张是一个标志。 培养的肾小球细胞的研究已经贡献 我们对肾小球功能的理解很大。 中键 细胞不仅响应血管活性剂，还会产生 前列腺素，PAF，细胞因子和基质成分。 肾小球细胞 还能够对大分子的特异性内吞作用。 我们的礼物 关于DM和DM中蛋白质非酶糖基化的知识 肾小球肾小球细胞的多个功能提供了清晰的 拟议研究的理由。 使用培养的介质 细胞和定义的蛋白质允许对个体进行实验解剖 因素，一种无法在体内采用的方法。 中央 要检验的假设是： 肾小球的晚期非酶糖基化产物的形成 基质蛋白和循环血浆过多的糖基质蛋白 蛋白质影响肾小球细胞功能，导致病理 糖尿病肾脏中膜的扩张。 为了测试 这个假设，我们将研究以下具体问题 培养的大鼠肾小球细胞：1）非酶糖基化会改变 蛋白质（例如白蛋白，IgG和低密度）的结合和摄取 脂蛋白通过肾小球细胞？ 2）进行非酶糖基化（AS 每个问题1）通过通过 肾小球细胞并影响基质的产生？ 3）做 肾小球基质的高级糖基化改变了其消化 肾小球蛋白酶？ 4）肾小球基质的高级糖基化 影响细胞增殖，细胞因子和基质的表达 成分？ 这些问题的答案应洞悉 蛋白质非酶糖基化的后果 肾小球积累，肾小球矩阵和胶原蛋白的产生， 因此，最终在糖尿病性肾小球硬化症上。 这应该允许 识别潜在的致病步骤，最终可能 帮助设计有针对性的治疗干预措施。