title: Angiopoietin correlates with glomerular capillary loss in anti-glomerular basement membrane glomerulonephritis.
abstract: BACKGROUND
  Emerging evidence suggests that endothelial turnover occurs in several glomerular diseases and correlates with resolution or progression of glomerular lesions. We hypothesized that the growth factors modulating embryonic kidney endothelial cell survival and capillary morphogenesis may be implicated in capillary loss that occurs in immune-mediated glomerulonephritis (GN).
  
  
  METHODS
  GN was induced in C57BL/6 mice by intravenous administration of sheep anti-mouse glomerular basement membrane (GBM) globulin and assessed with markers of vascularity in glomerular lesions, correlating these with expression of specific vascular growth factors.
  
  
  RESULTS
  As assessed by periodic acid Schiff staining, 14 +/- 4% (mean +/- SD) glomeruli were affected by sclerosis at 14 days after globulin administration, and 33 +/- 5% were affected at 21 days. By 21 days, a significant increase of plasma creatinine and urinary protein occurred. P-selectin expression was increased in glomerular capillaries 14 days after disease induction, and capillary loss, as assessed by immunohistochemistry for platelet-endothelial cell adhesion molecule, vascular endothelial growth factor (VEGF) receptor 2 and the angiopoietin (Ang) receptor Tie-2, was recorded at 14 and 21 days in glomeruli affected by proliferative crescents and/or sclerosis. VEGF-A immunostaining, evident in control glomeruli, was qualitatively diminished in glomeruli with lesions. Ang-1 immunostaining was detected in control glomeruli and was diminished at 14 days after administration of anti-mouse GBM globulin; instead, Ang-1 was immunolocalized to distal tubules. In contrast, Ang-2 immunostaining was barely detectable in control glomeruli but was prominent in disease glomeruli. In GN mice, rare apoptotic glomerular endothelia were detected by electron microscopy and in situ end-labeling, but such cells were not seen in controls.
  
  
  CONCLUSIONS
  Loss of glomerular capillaries during the course of anti-GBM GN in mice was temporally associated with decreases in endothelial survival molecules VEGF-A and Ang-1, and with up-regulation of Ang-2, an antagonist of Ang-1. A changing balance of these growth factors may contribute to decreased glomerular vascularity in crescentic GN.
authors.affiliation: Nephro-Urology Unit, Institute of Child Health, University College London, London, England, United Kingdom. hyuan@ich.ucl.ac.uk
authors.forename: Hai Tao
authors.initials: HT
authors.lastname: Yuan
authors.forename: Peter G
authors.initials: PG
authors.lastname: Tipping
authors.forename: Xiao Zhong
authors.initials: XZ
authors.lastname: Li
authors.forename: David A
authors.initials: DA
authors.lastname: Long
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
mesh_terms: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000378:metabolism* / Q000473:pathology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002196:Capillaries / Q000473:pathology; D016228:Endothelial Growth Factors / Q000378:metabolism; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000098:blood supply*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; D016228:Endothelial Growth Factors; D008562:Membrane Glycoproteins; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A