Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1.
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| Abstract |
Few studies have examined the role of the microvasculature in progressive renal disease. It was hypothesized that impaired angiogenesis might occur in the diseased kidney and could contribute to renal scarring. Progressive renal disease was induced in rats by 5/6 renal ablation and those rats were compared with sham-operated control animals at multiple time points, for examination of changes in the microvasculature and the expression of angiogenic factors. An early angiogenic response was documented in remnant kidneys, with increases in the proliferation of peritubular (1 wk) and glomerular (2 wk) endothelial cells. Subsequently, however, there was a decrease in endothelial cell proliferation, which was reduced to levels below those of sham-treated animals, in conjunction with interstitial expression of the antiangiogenic factor thrombospondin-1 (TSP-1) and decreased tubular expression of the proangiogenic factor vascular endothelial growth factor (VEGF). Both the increase in TSP-1 expression and the loss of VEGF expression were correlated with capillary loss and the development of glomerulosclerosis and interstitial fibrosis. Progressive macrophage infiltration was correlated both spatially and quantitatively with the sites of absent or diminished VEGF expression. In addition, macrophage-associated cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha) inhibited VEGF mRNA expression and protein secretion by cultured tubular epithelial cells of the medullary thick ascending limb, under both normoxic and hypoxic conditions. Impaired angiogenesis characterizes the remnant kidney model and is correlated with progression. The impaired angiogenesis may be mediated by alterations in the renal expression of TSP-1 and VEGF, with the latter being regulated by macrophage-associated cytokines.
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| Authors | Duk-Hee Kang, Alison H Joly, Se-Woong Oh, Christian Hugo, Dontscho Kerjaschki, Katherine L Gordon, Marilda Mazzali, J Ashley Jefferson, Jeremy Hughes, Kirsten M Madsen, George F Schreiner, Richard J Johnson |
| Journal | Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 12 Issue 7 Pg. 1434-1447 (Jul 2001) ISSN: 1046-6673 [Print] United States |
| PMID | 11423572 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.) |
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