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 μm) was selectively decreased in hypercholesterolemia plus thalidomide and accompanied by a decreased fraction of angiogenic, integrin β3-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-α 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.
|Original language||English (US)|
|Number of pages||8|
|State||Published - Oct 2007|
ASJC Scopus subject areas
- Internal Medicine