Journal Article

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

Taku Morita, Yoshihiko Kakinuma, Atsushi Kurabayashi, Mikiya Fujieda, Takayuki Sato, Taro Shuin, Mutsuo Furihata and Hiroshi Wakiguchi

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 26, issue 12, pages 4023-4031
Published in print December 2011 | ISSN: 0931-0509
Published online April 2011 | e-ISSN: 1460-2385 | DOI:
Conditional VHL gene deletion activates a local NO–VEGF axis in a balanced manner reinforcing resistance to endothelium-targeted glomerulonephropathy

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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, Nϖ-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.

Keywords: Habu snake venom glomerulonephropathy; nitric oxide; vascular endothelial growth factor

Journal Article.  5364 words.  Illustrated.

Subjects: Nephrology

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