Conditional VHL gene deletion activates a local NO-VEGF axis in a balanced manner reinforcing resistance to endothelium-targeted glomerulonephropathy

Nephrol Dial Transplant. 2011 Dec;26(12):4023-31. doi: 10.1093/ndt/gfr176. Epub 2011 Apr 14.

Abstract

Background/aims: We have reported that tubular epithelial cell injury caused by renal ischemia-reperfusion is attenuated in conditional VHL knockout (VHL-KO) mice and also that induction of hypoxia-inducible factor (HIF) suppresses angiotensin II-accelerated Habu snake venom (HV) glomerulonephropathy in rats. However, it remains unknown whether VHL knockdown protects glomerular endothelial cells from endothelium-targeted glomerulonephritis.

Methods and results: VHL-KO mice with HV glomerulonephropathy (HV GN) had fewer injured glomeruli, a lower mesangiolysis score and reduced blood urea nitrogen levels. Immunoreactivity of vascular endothelial growth factor (VEGF) in the glomerular capillaries was enhanced by VHL knockdown and was conserved even in VHL-KO mice with HV GN, despite HV-attenuating endothelial VEGF expression in vitro. VHL-KO mice showed enhanced nitric oxide (NO) production in glomerular endothelial cells and tubular cells, associated with activated VEGF expression in the kidney (i.e. an activated NO-VEGF axis). The levels of NO in glomeruli and tubules were conserved even in mice with HV GN. In contrast, suppressing NO production in glomerular endothelial cells by an NO synthase inhibitor, N(ϖ)-nitro-L-arginase, completely blunted the protection of VHL-KO from HV GN. The activated NO-VEGF axis in the kidney of VHL-KO mice was also associated with an elevation in Flk-1 phosphorylation and increased levels of IL-10 and IP-10.

Conclusion: Conditional VHL knockdown may enhance the NO-VEGF axis and protect glomerular endothelial cells from HV GN, thereby providing resistance to injury of tubular epithelial cells and glomerular endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Endothelial Cells / physiology*
  • Gene Deletion*
  • Glomerulonephritis / genetics*
  • Humans
  • Mice
  • Nitric Oxide / physiology*
  • Vascular Endothelial Growth Factor A / physiology*
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*

Substances

  • Vascular Endothelial Growth Factor A
  • Nitric Oxide
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, mouse