Renal hypertrophy is a ubiquitous concomitant of human and experimental diabetic nephropathy. We propose that the hypertrophic response is a necessary predisposing condition for the development of diabetic nephropathy. The goal of these studies os to gain an understanding at a cellular and molecular level of the mechanisms underlying diabetic glomerular hypertrophy; the relationship to """"""""compensatory"""""""" hypertrophy; and the role of transcapillary hydraulic forces in initiating diabetic glomerular hypertrophy. We will employ Northern blot analysis, in situ (mRNA) hybridization, immunoblot and immunocytochemical techniques to determine the cellular localization, relative content and temporal profile of the alterations in content of a number of potential molecular effectors and targets of the hypertrophic response: specifically, Tyr(P) modified proteins, and a series of mRNAs whose expression is likely to be relevant to the cell growth and tissue remodeling required for hypertrophy. These studies will be carried out in kidney from rats with streptozotocin diabetes and after uninephrectomy; moreover, we will determine the effects of the two kidney Goldblatt model on the parameters outlined above, so as to define how the evolution of the cellular response induced by diabetes os altered by systemic (and presumably glomerular) hyperperfusion (unclipped kidney) versus hypoperfusion (clopped kidney). In order to understand the regulatory mechanisms which underlie the changes we observe in the in vivo models, we will examine, in isolated glomerular cells, the response of these Tyr(P) and mRNA targets to treatment with a variety of hormones, growth factors, and second messenger analogs, singly and in combination. We will use these data to identify the cellular targets and intracellular mechanisms that are critical to the development of diabetic renal hypertrophy, so as to design selective and specific interventions.
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