Glomerular and Tubular Function in the Diabetic Kidney

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DESCRIPTION (provided by applicant): Diabetes mellitus is the commonest and fastest growing cause of end-stage renal disease in the developed world. Most ongoing laboratory and clinical research into the diabetic kidney focuses on injury and scarring that begin after 15-20 years of diabetes. However, the original idea that an early hemodynamic phenotype provokes the subsequent demise of a diabetic kidney continues to justify interest in the earlier stages of diabetes. Early diabetes is characterized by both glomerular hyper filtration and increased kidney size. Early diabetes also modifies the renal vascular response to a variety of physiologic stimuli including changes in perfusion pressure, salt intake, protein feeding, and exogenous insulin. While intrarenal hemodynamic abnormalities are potentially critical to the pathogenesis of diabetic nephropathy, the elemental cause of these abnormalities is poorly understood. It is the main purpose of this research to understand the cardinal renal hemodynamic abnormalities that occur at the start of diabetes, long before the onset of kidney damage. The foundation for this competing renewal rests on observations made during the last funding period. A central theme is that apparent abnormalities of glomerular function in early diabetes often represent a physiologic response of the glomerulus to primary abnormalities in the proximal tubule or loop of Henley that impact the glomerulus by feedback through the macula densa. Utilizing rats and mice with early streptozotocin diabetes, data will be obtained on nephron function by renal micropuncture, on functional genomics by laser capture micro dissection followed by quantitative RTPCR, and on protein expression by immunohistochemistry. The Specific Aims are: 1) To answer key questions regarding factors that drive kidney growth in early diabetes, and 2) To answer key questions regarding peculiarities of tubular reabsorption and the functional interactions between the tubule and glomerulus that occur in early diabetes.