MECHANISMS OF RADIATION-INDUCED KIDNEY INJURY

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DESCRIPTION: (Adapted from the applicant's abstract): Radiation-induced renal injury is a major complication of radiotherapy, particularly in patients subjected to total body irradiation for bone marrow transplantation. The nephropathy may progress to end stage renal disease. Because of the growing number of bone marrow transplants performed, characterization and prevention of progression of radiation nephropathy is of major concern. There is a big gap in our understanding of the injury and causing its progression to irreversible stages. Extracellular matrix synthesis (scarring) in renal glomerular capillary and endothelial injury are key characteristics. Glomerular scarring is indicative of enhanced expression and synthesis of factors that promote fibrogenesis. On the other hand, injury of the glomerular capillary endothelium may indicate that the synthesis of endothelium-derived factors may become perturbed thereby causing renal hemodynamic impairment. We have shown that angiotensin II (AII) synthesis inhibition preserves renal function and structure in a rat model of radiation nephropathy. This implicates biologic events triggered by AII as potential mechanisms underlying the pathogenesis of radiation nephropathy. Two likely events are, synthesis of the ECM promoting factor Transformng Growth Factor (TGF)-b1 and generation of the endothelium-derived vasodilator, nitric oxide. The proposed studies will use a rat model of radiation nephropathy to test the following hypotheses: 1) In radiation-induced nephropathy there is enhanced synthesis of specific extracellular matrix (ECM) proteins and enhanced expression of TGF-b1 which promotes synthesis of these ECM proteins. AII inhibition attenuates TGF-b1 expression and synthesis of ECM proteins. 2) In radiation-induced nephropathy there is injury of the glomerular capillary endothelium. This results in impaired production of the endothelium-derived vasodilator, nitric oxide (NO), thereby changing pressures and flows in the glomerular microvasculature. AII synthesis inhibition restores or promotes NO generation thereby ameliorating renal ischemia. It is anticipated that the observations will enhance our understanding of the pathobiology of radiation-induced injury and provide means to avert its progression to irreversible stages.