Hypercholesterolemia induces renal
inflammation and neovascularization, associated with renal endothelial dysfunction and injury. Neovascularization might conceivably represent a defense mechanism to sustain renal perfusion. Therefore, the present study was designed to test the hypothesis that preventing neovascularization using
thalidomide, a potent anti-inflammatory and
antiangiogenic agent, would impair basal renal hemodynamics in experimental
hypercholesterolemia.
Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 weeks of
hypercholesterolemia,
hypercholesterolemia chronically supplemented with
thalidomide (4 mg/kg per day), and normal controls. Renal microvascular architecture was then studied ex vivo using 3D microcomputed tomography imaging and
inflammation, angiogenesis, and oxidative stress explored in renal tissue. The density of larger microvessels (200 to 500 microm) was selectively decreased in
hypercholesterolemia plus
thalidomide and accompanied by a decreased fraction of angiogenic,
integrin beta(3)-positive microvessels (9.9%+/-0.9% versus 25.5%+/-1.7%; P<0.05 versus
hypercholesterolemia), implying decreased angiogenic activity. Furthermore,
thalidomide increased renal expression of endothelial
NO synthase and decreased
tumor necrosis factor-alpha and renal
inflammation but did not decrease oxidative stress.
Thalidomide also decreased basal renal blood flow and glomerular filtration rate but normalized the blunted renal hemodynamic responses in
hypercholesterolemia. Attenuated
inflammation and
pathological angiogenesis achieved in
hypercholesterolemia by
thalidomide are accompanied by restoration of renovascular endothelial function but decreased basal renal hemodynamics. This study, therefore, suggests that neovascularization in the hypercholesterolemic kidney is a compensatory mechanism that sustains basal renal vascular function.