Pathogenesis of Diabetic Nephropathy

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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.