This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetic nephropathy (DN) is the leading cause of renal failure, yet pathogenetic understanding remains limited. Objectives of these studies are (a) to develop risk markers based on in vitro studies of cells derived from individual insulin dependent diabetic (IDDM) patients, which are related to renal biopsy endpoints, (b) to ask if these markers represent genetically determined processes and (c) to define relationships between cellular (in vitro) expression of mRNA for extracellular martix (ECM) molecules, their enzymes and enzyme regulators, growth factors, glucose transporters, and sodium/hydrogen antiporter and renal structural and functional endpoints in order to explore basic pathogenic mechanisms in DN; to develop a repository of DNA and cultured cells that will allow evaluation of the cellular functional consequences of genetic variations shown to be linked to DN risk. Three patient groups will be studied: (a) early (~10 years) and long-term (~20 years) IDDM duration patients dichotomized into 2 groups with slow or rapid development of DM lesions, (b) sibling pairs concordant for IDDM, and (c) identical twins discordant for IDDM. DN will be quantitated morphometrically, and factored for duration or expressed as a rate determined by 2 biopsies 5 years apart. The primary endpoint will be mesangial volume fraction [Vv(Mes/glom)] measured by electron microscopic morphometric analysis. Cross-sectional studies of long-term IDDM patients will allow the identification of cellular markers associated with very rapid or very slow development of DN lesions and clinical renal abnormalities. Longitudinal studies (5 year) in shorter-term 'fast' and 'slow-track' patients and IDDM sibling pairs will allow factoring for glycemia and blood pressure and other 'environmental variables.' Cultured skin fibroblasts (SF) from individual patients will be evaluated for mRNA expression for the above listed molecules using reverse transcriptase polymerase chain reaction. SF are selected since changes in their phenotype occur in 'fast-track' IDDM patients and are correlated in sibling pairs. These studies will determine the relationship of DN lesions to SF behavior and evaluate whether this behavior is concordant in IDDM sibling pairs who are concordant for DN lesions. SF from nondiabetic identical twins will answer whether hyperglycemia is necessary for the expression of cellular markers of DN risk.
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