Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor

Gaetano Faleo, Joao Seda Neto, Junichi Kohmoto, Koji Tomiyama, Hiroko Shimizu, Toru Takahashi, Yinna Wang, Ryujiro Sugimoto, Augustine M.K. Choi, Donna B. Stolz, Giuseppe Carrieri, Kenneth R. McCurry, Noriko Murase, Atsunori Nakao

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Abstract

BACKGROUND.: We have previously shown that carbon monoxide (CO) inhalation at a low concentration provides protection against cold ischemia-reperfusion (I/R) injury after kidney transplantation. As vascular endothelial growth factor (VEGF) may promote the recovery process of impaired vascular endothelial cells during I/R injury, we examined whether protective effects of CO involved VEGF induction and its upstream hypoxia-inducible factor (HIF)-1 activation. METHODS.: Lewis rat kidney graft, preserved in University of Wisconsin at 4°C for 24 hr, was orthotopically transplanted into syngeneic recipient. Recipients were continuously maintained in air or exposed to CO (250 ppm) for 1 hr before and 24 hr after transplant. RESULTS.: Prolonged cold preservation resulted in progressive impairment of kidney graft function with early inflammatory responses. Carbon monoxide significantly protected kidney grafts from cold I/R injury, improved renal function and enhanced recipient survival. Real-time reverse transcriptase-polymerase chain reaction revealed upregulation of HIF-1α and VEGF in the CO-treated kidney grafts as early as 1 hr after reperfusion. Western blot showed CO significantly upregulated VEGF expression 1 to 3 hr after kidney transplantation. Considerably more VEGF-positive cells were observed mainly in tubular epithelial cells in CO-treated, but not air-exposed, kidney grafts at 3 hr after reperfusion. YC-1, HIF-1α inhibitor, completely abrogated the actions of CO on VEGF induction and reversed the protective effects afforded by CO. Nitric oxide production in the grafts was increased by CO, however, abolished by YC-1. CONCLUSION.: These results demonstrate that the protective effect of CO against renal cold I/R injury may involve VEGF upregulation through its upstream signal, HIF-1 activation.

Original languageEnglish
Pages (from-to)1833-1840
Number of pages8
JournalTransplantation
Volume85
Issue number12
DOIs
Publication statusPublished - Jun 27 2008
Externally publishedYes

Keywords

  • Carbon monoxide
  • Hypoxia-inducible factor
  • Ischemia/reperfusion injury
  • Renal transplantation
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Transplantation

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  • Cite this

    Faleo, G., Neto, J. S., Kohmoto, J., Tomiyama, K., Shimizu, H., Takahashi, T., Wang, Y., Sugimoto, R., Choi, A. M. K., Stolz, D. B., Carrieri, G., McCurry, K. R., Murase, N., & Nakao, A. (2008). Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor. Transplantation, 85(12), 1833-1840. https://doi.org/10.1097/TP.0b013e31817c6f63