MECHANISMS OF RENAL IMPAIRMENT IN HYPERCHOLESTEROLEMIA

DESCRIPTION: (Adapted from the Investigator's Abstract): This proposal deals with injurious effects of hypercholesterolemia (HC) on the kidney that can be detected in vivo and in vitro during an early phase of functional abnormalities in the renal vasculature and tubules. Pigs (females) on a HC diet consisting of 2% cholesterol + 15% lard for 12 weeks. The roles of pro-oxidant state related increase in the oxidation of low-density lipoproteins and local activation by the renin-angiotensin system is assessed by measurements of plasma concentrations of peroxynitrite and isoprostanes (PGF2alpha). Renal hemodynamics and tubular function are examined using an electron-beam computer tomography (EBCT; Imatron C-150) in conjunction with intravenous injection of non-ionic, low osmolar contrast medium (iopamidol). Vascular reactivity of isolated renal vessels is also tested. Vascular structure is examined using micro-computed tomography to reconstruct 3-dimentional casts of the intrarenal vasculature. Comparisons are made with conventional histological sections. Aim # 1 is to define patterns changes in the structure and function of vessels and tubules in the kidneys of swine fed HC diet for 12 weeks. In vivo and in vitro measures will be correlated with the oxidative state assessed by plasma and renal tissue concentrations of isoprostanes. Selectivity of impaired endothelium-dependent relaxation to acetylcholine will be compared to smooth muscle relaxation produced by sodium nitroprusside, an NO donor. Vascular reactivity to free isoprostanes will be compared to the thromboxane mimetic U46619. Aim # 2 is to examine mechanisms involved in the renal abnomalities. Effects of HC are to be reversed by blocking for 8 weeks (total of 20 weeks of HC diet) angiotensin AT1 receptors (ibresartan) or oxidative pathway (vitamins E + C; oxypurinol inhibition of xanthine oxidase). Aim 3 studies will test reversibility by normalization of lipid diet or treatment with a cholesterol-lowering drug (simvastatin, an HMG-COA reductase inhbitor,). Aim # 4 is to characterize intrarenal morphology in the HC pig model using 3-d x-ray micro-CT of microfil vascular casts and conventional light microscopy histology of tissue sections.