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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL063282-01A1
Application #
6091037
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Scherbenske, M James
Project Start
2000-05-01
Project End
2004-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$211,650
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Pilarczyk, Kevin; Sattler, Katherine J E; Galili, Offer et al. (2008) Placenta growth factor expression in human atherosclerotic carotid plaques is related to plaque destabilization. Atherosclerosis 196:333-40
Versari, Daniele; Gossl, Mario; Mannheim, Dallit et al. (2007) Hypertension and hypercholesterolemia differentially affect the function and structure of pig carotid artery. Hypertension 50:1063-8
Daghini, Elena; Juillard, Laurent; Haas, John A et al. (2007) Comparison of mathematic models for assessment of glomerular filtration rate with electron-beam CT in pigs. Radiology 242:417-24
Versari, Daniele; Daghini, Elena; Rodriguez-Porcel, Martin et al. (2006) Chronic antioxidant supplementation impairs coronary endothelial function and myocardial perfusion in normal pigs. Hypertension 47:475-81
Rodriguez-Porcel, Martin; Zhu, Xiang-Yang; Chade, Alejandro R et al. (2006) Functional and structural remodeling of the myocardial microvasculature in early experimental hypertension. Am J Physiol Heart Circ Physiol 290:H978-84
Sattler, Katherine J E; Galili, Offer; Rodriguez-Porcel, Martin et al. (2006) Dietary reversal of experimental hypercholesterolemia improves endothelial dysfunction of epicardial arteries but not of small coronary vessels in pigs. Atherosclerosis 188:301-8
Zhu, Xiang-Yang; Daghini, Elena; Chade, Alejandro R et al. (2006) Role of oxidative stress in remodeling of the myocardial microcirculation in hypertension. Arterioscler Thromb Vasc Biol 26:1746-52
Chade, A R; Brosh, D; Higano, S T et al. (2006) Mild renal insufficiency is associated with reduced coronary flow in patients with non-obstructive coronary artery disease. Kidney Int 69:266-71
Daghini, Elena; Chade, Alejandro R; Krier, James D et al. (2006) Acute inhibition of the endogenous xanthine oxidase improves renal hemodynamics in hypercholesterolemic pigs. Am J Physiol Regul Integr Comp Physiol 290:R609-15
Galili, Offer; Sattler, Katherine J; Herrmann, Joerg et al. (2005) Experimental hypercholesterolemia differentially affects adventitial vasa vasorum and vessel structure of the left internal thoracic and coronary arteries. J Thorac Cardiovasc Surg 129:767-72

Showing the most recent 10 out of 52 publications