Hypertrophy of the kidney occurs in several conditions, including diabetes mellitus. In such conditions, there must be an imbalance between renal protein synthesis (PS) and degradation (PD) so that PS is stimulated and/or PD is inhibited to yield an increase in tissue mass. This creates an apparent paradox since insulin stimulates PS and inhibits PD in other tissues, yet in the kidney, a deficit of insulin causes hypertrophy. The solution is unknown because there have been few measurements of the components of renal protein turnover or how insulin affects them. The proposed studies will develop methods for measuring PS and PD in incubated rat proximal tubules; incorporation of 14C- phenylalanine into protein will be used to estimate PS and the met release of lysine to estimate PD. We will then determine how diabetes and insulin affect renal protein turnover. Since tyrosine phosphorylation has been associated with hypertrophic stimuli in other tissues, we will determine if it is increased in the renal hypertrophy of diabetes. If in situ phosphorylation of tubule proteins is increased by diabetes, we will determine whether this is related to decreased activity of tyrosine phosphorprotein phosphatases and/or increased tyrosine kinase activity. To address the other possibility, tyrosine kinase activity of the insulin, IGF-I and IGF-II receptors, isolated from tubule membranes by affinity chromatography, will be measured. Ligand binding, receptor autophosphorylation and tyrosine kinase activities will be related to changes in PS and PD induced by diabetes. The specificity of the changes induced by diabetes will be assessed by comparing the response in both kidneys of a two- kidney, one-clop model of hypertension in rats with or without diabetes. Using paired analyses, the influence of hyperperfusion can be assessed and compared to results from pair-fed uninephrectonized and control rats to determine if there is a separate hypertrophic influence of hypertension. These results could elucidate the influence of insulin and hypertension on renal tubule protein turnover and yield insight into the mechanisms of renal tubule hypertrophy in diabetes.

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