Pathogenesis of Diabetic Nephropathy

描述(申请人提供)：糖尿病肾病表现为 与高血糖有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，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 二甘油二酯的合成、蛋白激酶C的活化及其形成 早期糖基化产物。后者导致了高级 糖基化产物，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。 多元醇途径受限速酶--醛糖还原酶的调节 (AKR1B)，参与葡萄糖还原为山梨醇和 NADPH作为脱毒剂对活性羰基和脂二醛的脱毒作用 辅因。AKR1B的普遍分布表明， 多元醇途径在许多组织中都是可操作的，因此人们可以预料到 糖尿病的多器官损害，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已经被 在本实验室分离得到，命名为肾脏特异性氧化还原酶 (RSOR)。初步研究表明，它与AKR1B有一些相似之处， 它有一个醛酮还原酶-3催化基序，与NADPH结合 高亲和力及其表达在高血糖时上调。因此， 可以想象，这种定位于22号染色体的酶可能与 人类胚胎和成年时期糖尿病的肾脏并发症。至 为了证明这一论点，在5个具体项目下提出了一系列实验 目标如下： 第一，从肾脏中分离的RSOR的特性及其重组 技术将会被实施。 II.分离的RSOR将用于鉴定各种底物和 对其催化基序的分析。 生病了。这一目标将致力于确定导致 在体外/体内上调RSOR。 +_ 四、RSOR及其ITS基因5‘和3’侧翼区的特征 将对基因组组织进行研究。 五、它在正常血糖和高血糖后肾发生中的调节 各州将受到调查。

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.