Pathogenesis of Diabetic Nephropathy

糖尿病肾病的发病机制

• 批准号: 7002705
• 负责人: Yashpal S. Kanwar
• 金额: $ 31.02万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002705
• 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 诱导事件，并导致多元醇的活性增加 途径、NADPH/NADP+ 比率改变、肌醇池耗尽、增加 二酰甘油的合成、蛋白激酶C的激活和形成 早期糖化产物。后者导致先进的产生 糖化产物，通过几种不同的机制导致异常 细胞外基质蛋白的合成与随后的糖尿病肾病有关。 多元醇途径受限速酶醛糖还原酶调节 (AKR1B)，参与葡萄糖还原为山梨醇和 利用 NADPH 作为活性羰基和脂二醛的解毒 辅因子。 AKR1B 的普遍分布表明 多元醇途径在许多组织中起作用，因此人们可以预期 糖尿病患者的多个器官都会受到损害，尽管损害的程度 可能与其在特定器官系统中的表达程度有关。最近， 一种仅在肾脏中表达的氧化还原酶 在我们实验室分离，并被指定为肾特异性氧化还原酶 （RSOR）。初步研究表明它与 AKR1B 有一些相似之处，即 也就是说，它具有醛酮还原酶 3 催化基序，可与 NADPH 结合 高亲和力，其表达在高血糖时上调。因此， 可以想象，这种酶位于 22 号染色体上，可能与 人类胚胎期和成年期糖尿病的肾脏并发症。到 为了证明这一论点，我们在 5 个具体条件下提出了一系列实验 目标如下： I. 首先，从肾脏分离并重组的 RSOR 的表征 将进行技术。 二.隔离的 RSOR 将用于识别各种基材和 分析其催化基序。 III. 这一目标将致力于确定导致 RSOR 体外/体内上调。 + __ _____ __ ____ 四．在此目标中，RSOR 的 5' 和 3' 侧翼区域的特征及其 将研究基因组组织。 五、最后，其在血糖正常和高血糖情况下对后肾发生的调节 各州将接受调查。