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Study for model of diabetic nephropathy and prevention of disease progress

糖尿病肾病模型及预防疾病进展的研究

基本信息

批准号：
06557064
负责人：
DOI Toshio
金额：
$ 7.87万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

Diabetic nephropathy is one of the most important diseases for cause of endstage kidney disease. The pathogenesis and treatment of the disease are critical for medical and social problems. Diabetic complications are mediated by advanced glycation endproducts (AGE) which produced by long-term reaction between proteins and high glucose condition. This study was designed to establish the model of diabetic nephropathy and to study the mechanism and the prevention of disease progress. We analyzed knockout mice for apolipoprotein E that developed the progressive glomerulosclerosis in association with glomerular hypertrophy. Mesangial cells had a low affinity receptor for AGE (RAGE) and increased the synthesis of extracellular matrix including type IV collagen. This reaction was mediated by specific DNA binding protein for promoter of type IV collagen (Alp145), which had multifunctions including DNA replication factor C and DNA binding proteins for promoter of angiotensinogen. The expression … More of Alp145 was correlated with glomerular sclerosis and cell proliferation in vivo model. Furthermore, we applied the hammerhead ribozyme for targeting RAGE and established a stable cell line that produced RAGE-specific ribozyme. The induction of type IV mRNA by AGE on mesangial cell was inhibited by RAGE-specific ribozyme. Heat shock protein 47 (HSP47) is a collagen-specific chaperone that has a major role during the biosynthesis and secretion of procollagen molecules. The expression of HSP47 increased in parallel with the expression of collagens during the progression of glomerulosclerosis in renal ablation rats. The administration of antisense oligonucleotides against HSP47 at the induction of anti-thy-1 glomerulonephritis markedly suppressed the increased production of collagens and attenuated the histological manifestations of desease. This study provides to establish the model for typical glomerulosclerosis, to determine the mechanisms of disease progression, and to further develop new strategy for prevention of disease progression. Less

糖尿病肾病是终末期肾病的重要病因之一。该病的发病机制和治疗是医学和社会问题的关键。糖基化终末产物（AGE）是蛋白质与高糖长期反应产生的产物，是糖尿病并发症的重要介导因素。本研究旨在建立糖尿病肾病模型，探讨糖尿病肾病的发病机制及防治措施。我们分析了敲除载脂蛋白E的小鼠，这些小鼠发展为与肾小球肥大相关的进行性肾小球硬化。系膜细胞对AGE（AGE）有低亲和力受体，并增加细胞外基质（包括IV型胶原）的合成。该反应由IV型胶原启动子特异性DNA结合蛋白（Alp 145）介导，Alp 145具有DNA复制因子C和血管紧张素原启动子DNA结合蛋白等多功能。表达 ...更多信息 Alp 145的表达与肾小球硬化和细胞增殖相关。此外，我们将锤头状核酶应用于靶向RAGE，并建立了稳定的产生RAGE特异性核酶的细胞系。RAGE特异性核酶可抑制AGE对系膜细胞IV型mRNA的诱导。热休克蛋白47（HSP 47）是一种胶原特异性分子伴侣，在前胶原分子的生物合成和分泌过程中起重要作用。在肾切除大鼠肾小球硬化过程中，HSP 47的表达与胶原的表达呈平行增加。在诱导抗Thy-1肾小球肾炎时给予HSP 47的反义寡核苷酸可明显抑制胶原的产生，减轻疾病的组织学表现。本研究为建立典型肾小球硬化模型，探讨疾病进展机制，进一步开发预防疾病进展的新策略提供了实验依据。少