Angiopoietin correlates with glomerular capillary loss in anti-glomerular basement membrane glomerulonephritis

Kidney Int. 2002 Jun;61(6):2078-89. doi: 10.1046/j.1523-1755.2002.00381.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-1
  • Angiopoietin-2
  • Animals
  • Anti-Glomerular Basement Membrane Disease / metabolism*
  • Anti-Glomerular Basement Membrane Disease / pathology*
  • Blotting, Northern
  • Blotting, Western
  • Capillaries / pathology
  • Endothelial Growth Factors / metabolism
  • Immunohistochemistry
  • Kidney Glomerulus / blood supply*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Proteins / metabolism*
  • Vascular Endothelial Growth Factor A

Substances

  • Angiopoietin-1
  • Angiopoietin-2
  • Angpt1 protein, mouse
  • Endothelial Growth Factors
  • Membrane Glycoproteins
  • Proteins
  • Vascular Endothelial Growth Factor A