Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1.
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.
Kang
Duk-Hee
DH
Division of Nephrology, University of Washington, Seattle, Washington.
Joly
Alison H
AH
Scios, Inc., Sunnyvale, California.
Oh
Se-Woong
SW
Division of Nephrology, University of Washington, Seattle, Washington.
Hugo
Christian
C
Division of Nephrology, University of Erlangen, Erlangen, Germany.
Kerjaschki
Dontscho
D
Department of Clinical Pathology, University of Vienna, Vienna, Austria.
Gordon
Katherine L
KL
Division of Nephrology, University of Washington, Seattle, Washington.
Mazzali
Marilda
M
Division of Nephrology, University of Washington, Seattle, Washington.
Jefferson
J Ashley
JA
Division of Nephrology, University of Washington, Seattle, Washington.
Hughes
Jeremy
J
Division of Nephrology, University of Washington, Seattle, Washington.
Madsen
Kirsten M
KM
Division of Nephrology, University of Florida, Gainesville, Florida.
Schreiner
George F
GF
Scios, Inc., Sunnyvale, California.
Johnson
Richard J
RJ
Division of Nephrology, University of Washington, Seattle, Washington.
D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D016207:Cytokines / Q000502:physiology; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000503:physiopathology*; D008138:Loop of Henle / Q000166:cytology / Q000378:metabolism; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008833:Microcirculation; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009392:Nephrectomy; D011507:Proteinuria / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D051437:Renal Insufficiency / Q000473:pathology / Q000503:physiopathology; D019700:Thrombospondin 1 / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016207:Cytokines; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors