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， 其次是明显的蛋白尿和终末期肾功能衰竭。几个 组织学异常发展；然而，进行性的 系膜基质的膨胀是导致消亡的原因 肾小球滤过的毛细血管管腔和丢失。它是 本提案的目的是定义异常的那些特征 促进糖尿病发展的代谢环境 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 肾小球系膜基质胶原的表达 糖尿病肾病肾小球硬化。这一假说将 通过以下具体目标进行测试： 目标1.初步数据表明，胰岛素 治疗与增加系膜细胞合成有关 基质胶原与胶原表型的变化 产生(类型IV到类型III)。这些观察结果将是 经肾小球结构的组织形态计量学分析证实 并分析了生理盐水胶原蛋白表型的表达 胰岛素治疗正常大鼠和糖尿病大鼠。 目的2.明确胰岛素和胰岛素的特殊影响 胰岛素样生长因子(IGF)对胶原合成率和 培养的大鼠肾小球系膜细胞的图谱。 目标3.确认那些刺激和 基质合成和体外表型的增加有助于 肾小球系膜基质在体内的积累。关联性将 在血清胰岛素、血糖和IGF值之间进行比较， 肾小球IGF的产生与系膜基质的程度 组织中III型胶原基因的扩增和表达 取自对照组和糖尿病大鼠。 目的4.确定糖尿病的生物学效应 系膜基质改变对系膜细胞功能的影响。 系膜细胞的附着、增殖和分泌表型 将细胞导入正常细胞和改变的细胞外--无细胞 矩阵将被确定。 对影响他的代谢因素的定义 系膜硬化症的发展和进展应导致 预防糖尿病肾病的策略。

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.