MESANGIAL MATRIX EXPANSION IN DIABETES--ROLE OF IGF

糖尿病肾病的临床特征是 微量白蛋白尿和肾小球滤过率升高， 随后出现明显的蛋白尿和终末期肾衰竭。 几 组织学异常发展;然而，进行性 系膜基质的扩张是导致 毛细血管腔和肾小球滤过功能丧失。 是 本提案的目的是定义异常的这些特征， 糖尿病的代谢环境，有助于发展 系膜硬化症 假设：胰岛素治疗，直接或间接， 有助于增加合成和改变表型 系膜基质胶原蛋白的表达， 糖尿病肾病的肾小球硬化 这一假设将 通过以下具体目标进行测试： 目的1. 初步数据表明，胰岛素 治疗与肾小球系膜合成增加有关， 基质胶原和胶原表型的变化 生产（类型IV至类型III）。 这些观察将是 通过肾小球结构的组织形态学分析证实 以及分析来自盐水和 胰岛素治疗的正常和糖尿病大鼠。 目标2. 确定胰岛素的具体影响， 胰岛素样生长因子（IGF）对胶原蛋白合成速率的影响， 使用培养的大鼠肾小球系膜细胞的曲线。 目标3. 为了证实那些刺激 体外基质合成和表型增加有助于 肾小球系膜基质在体内的积聚。 相关性将 在血清胰岛素、葡萄糖和IGF值之间进行， 肾小球产生IGF，以及系膜基质的程度 组织中的扩增和III型胶原基因表达 从对照和糖尿病大鼠中收获。 目标4. 为了确定糖尿病的生物效应， 系膜基质改变对系膜细胞功能的影响。 系膜细胞的粘附、增殖和分泌表型 将细胞引入正常和改变的无细胞细胞外 矩阵将被确定。 这些代谢因素的定义，有助于他 系膜硬化的发展和进展应导致 糖尿病肾病的治疗方法有哪些

Diabetic nephropathy is clinically characterized by microalbuminuria and elevated glomerular filtration rate, followed by overt proteinuria and endstage renal failure. Several histological abnormalities develop; however, the progressive expansion of mesangial matrix is responsible for obliteration of the capillary lumena and loss of glomerular filtration. It is the purpose of this proposal to define those features of the abnormal metabolic milieu of diabetes that contribute to the development of mesangial sclerosis. Hypothesis: Insulin treatment, either directly or indirectly, contributes to the increased synthesis and altered phenotypic expression of mesangial matrix collagen which typifies the glomerulosclerosis of diabetic nephropathy. This hypothesis will be tested by the following specific objectives: Objective 1. Preliminary data have demonstrated that insulin treatment is associated with increased synthesis of mesangial matrix collagen and a change in the phenotype of collagen produced (type IV to type III). These observations will be confirmed by histomorphometric analysis of glomerular structures and analysis of expression of collagen phenotypes from saline and insulin-treated normal and diabetic rats. Objective 2. To define the specific influence of insulin and insulin-like growth factors (IGF) on collagen synthetic rates and profiles using cultured rat mesangial cells. Objective 3. To confirm that those factors which stimulate an increase in matrix synthesis and phenotype in vitro contribute to the accumulation of mesangial matrix in vivo. Correlations will be made between serum insulin, glucose and IGF values, glomerular production of IGF, and the degree of mesangial matrix expansion and type III collagen gene expression in tissues harvested from control and diabetic rats. Objective 4. To determine the biological effects of diabetically altered mesangial matrix on the function of mesangial cells. Attachment, proliferation and secretory phenotype of mesangial cells introduced onto normal and altered cell-free extra-cellular matrices will be determined. Definition of those metabolic factors which contribute to he development and progression of mesangial sclerosis should lead to strategies for the prevention of diabetic nephropathy.