MECHANISMS OF RENAL IMPAIRMENT IN HYPERCHOLESTEROLEMIA

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date5/1/004/30/06

Funding

  • National Heart, Lung, and Blood Institute: $211,650.00
  • National Heart, Lung, and Blood Institute: $211,650.00
  • National Heart, Lung, and Blood Institute: $211,650.00
  • National Heart, Lung, and Blood Institute: $211,650.00

ASJC

  • Medicine(all)

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