Pathogenesis of Diabetic Nephropathy

糖尿病肾病的发病机制

• 批准号: 6418396
• 负责人: Yashpal S. Kanwar
• 金额: $ 33.44万
• 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/6418396
• 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（由申请人提供）：糖尿病肾病反映了 与高血糖症相关的长期终末器官靶组织损伤。 显然，作为对高血糖的适应性反应，许多早期细胞 事件被诱导，并且它们导致多元醇的活性增加 途径，改变NADPH/NADP+比率，消耗肌醇池，增加 二酰基甘油的合成、蛋白激酶C的活化和 早期糖化产物后者导致了先进的一代 糖基化产物，其通过几种不同的机制引起异常的 细胞外基质蛋白的合成与随后的糖尿病肾病。 多元醇途径受一种限速酶--醛糖还原酶调节 （AKR 1B），其参与将葡萄糖还原成山梨糖醇， 活性羰基和脂质二醛的解毒，利用NADPH作为 的cofactor。AKR 1B的普遍分布表明， 多元醇途径在许多组织中起作用，因此可以预期 糖尿病多器官损害，虽然损害程度 可能与其在给定器官系统中的表达程度有关。最近， 一种只在肾脏中表达的氧化还原酶， 在我们的实验室分离，并指定为肾特异性氧化还原酶 （RSOR）。初步研究表明，它与AKR 1B有一些相似之处， 它具有醛酮还原酶-3催化基序， 高亲和力，且其表达在高血糖症中上调。因此，在本发明中， 可以想象，这种位于22号染色体上的酶可能与 糖尿病在人类胚胎期和成年期的肾脏并发症。到 为了证明这一论点，提出了一系列实验，在5个具体的 目标如下： I.首先，从肾脏分离的RSOR和通过重组的RSOR的表征， 技术将被执行。 二.分离的RSOR将用于鉴定各种底物， 分析其催化基序。 伊利诺伊州这一目标将致力于确定导致 体外/体内RSOR的上调。 + __ _____ __ ____ 四.为此，我们对RSOR基因5'和3'侧翼区的特征及其与基因表达的关系进行了研究。 将研究基因组结构。 V.最后，它在正常血糖和高血糖的后肾发生中的调节 各国将进行调查。