Pathogenesis of Diabetic Nephropathy

糖尿病肾病的发病机制

• 批准号: 6620309
• 负责人: Yashpal S. Kanwar
• 金额: $ 32.23万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620309
• 关键词: Baculoviridae; NAD(H) phosphate; aldehyde reductase; diabetes mellitus; diabetic nephropathy; enzyme activity; enzyme mechanism; enzyme substrate; genetic promoter element; genetically modified animals; glucose metabolism; histogenesis; hyperglycemia; kidney cell; laboratory mouse; laboratory rabbit; laboratory rat; nucleic acid sequence; oxidoreductase; pathologic process; renal glomerulus; renal tubule; tissue /cell culture; transfection /expression vector

DESCRIPTION (provided by applicant): Diabetic nephropathy reflects a longstanding end organ target tissue injury that is related to hyperglycemia. Apparently, as an adaptive response to hyperglycemia a number of early cellular events are induced, and they lead to an increased activity of the polyol pathway, altered NADPH/NADP+ ratio, depletion of myoinositol pools, increased synthesis of diacyiglycerol, activation of protein kinase C and formation of early glycation products. The latter leads to the generation of advanced glycation products, which via several different mechanisms cause an abnormal synthesis of extracellular matrix proteins with ensuing diabetic nephropathy. The polyol pathway is regulated by a rate limiting enzyme, aldose reductase (AKR1B), that is involved in the reduction of glucose to sorbitol and detoxification of reactive carbonyls and lipid dialdehydes, utilizing NADPH as the cofactor. The ubiquitous distribution of AKR1B would suggest that the polyol pathway is operative in many tissues, and as a result one may expect damage in multiple organs in diabetes mellitus, although the degree of damage may relate to the extent of its expression in a given organ system. Recently, an oxido-reductase that is exclusively expressed in the kidney has been isolated in our laboratory, and is designated as renal specific oxido-reductase (RSOR). Initial studies suggest that it has some similarities with AKR1B, that is, it has an aldo-keto reductase-3 catalytic motif that binds to NADPH with high affinity and its expression is up-regulated in hyperglycemia. Thus, conceivably, this enzyme, localized to the chromosome 22, may be related to the renal complications of diabetes both in embryonic and adult life in humans. To attest to this contention a series of experiments are proposed under 5 specific aims as follows: I. First, characterization of RSOR isolated from kidneys and by recombinant techniques will be carried out. II. The isolated RSOR will be used for identification of various substrates and analysis of its catalytic motif. Ill. This aim will be devoted to identify the mechanisms that lead to the upregulation of RSOR in vitro/in vivo. + __ _____ __ ____ IV. In this aim, characteristics of 5' & 3' flanking regions of RSOR & its genomic organization will be studied. V. Finally, its regulation in metanephrogenesis in euglycemic and hyperglycemic states will be investigated.

描述（申请人提供）：糖尿病性肾病反映了 与高血糖有关的长期末端器官靶组织损伤。 显然，作为对高血糖的适应性反应，许多早期细胞 事件是诱导的，它们导致多元醇的活性增加 途径，变化的NADPH/NADP+比率，肌醇池的耗竭，增加 二酰甘油的合成，蛋白激酶C的激活和形成 早期糖基产品。后者导致高级产生 糖化产物，通过几种不同的机制引起异常 与随后的糖尿病性肾病的合成细胞外基质蛋白。 多元途径由限制酶，醛糖还原酶的速率调节 （akr1b），与葡萄糖减少到山梨糖醇和 用NADPH作为反应性羰基排毒和脂质二醛 辅助因子。 AKR1B的普遍分布会表明 多元醇途径在许多组织中都是可操作的，因此可能期望 糖尿病中多个器官的损害，尽管损害程度 可能与它在给定器官系统中的表达程度有关。最近， 在肾脏中仅表达的氧化还原酶已经 在我们的实验室中孤立，被指定为肾脏特异性氧化还原酶 （RSOR）。最初的研究表明，它与AKR1B有一些相似之处 IS，它具有与NADPH结合的aldo-Keto还原酶3催化基序 高亲和力及其表达在高血糖中被上调。因此， 可以想象，该酶本地定位于22号染色体，可能与 人类胚胎和成人生活中糖尿病的肾脏并发症。到 证明这一争论是根据5个特定的一系列实验提出的一系列实验 目的如下： I.首先，从肾脏和重组分离的RSOR的表征 技术将进行。 ii。隔离的RSOR将用于识别各种底物和 分析其催化基序。 病。这个目标将致力于确定导致的机制 RSOR体外/体内的上调。 + __ _____ __ ____ iv。在此目标中，RSOR及其侧面的5'＆3'特征 将研究基因组组织。 V.最后，其在葡萄糖和高血糖中的跨化剂发生的调节 国家将进行调查。