TY - JOUR
T1 - Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor
AU - Faleo, Gaetano
AU - Neto, Joao Seda
AU - Kohmoto, Junichi
AU - Tomiyama, Koji
AU - Shimizu, Hiroko
AU - Takahashi, Toru
AU - Wang, Yinna
AU - Sugimoto, Ryujiro
AU - Choi, Augustine M.K.
AU - Stolz, Donna B.
AU - Carrieri, Giuseppe
AU - McCurry, Kenneth R.
AU - Murase, Noriko
AU - Nakao, Atsunori
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2008/6/27
Y1 - 2008/6/27
N2 - 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.
AB - 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.
KW - Carbon monoxide
KW - Hypoxia-inducible factor
KW - Ischemia/reperfusion injury
KW - Renal transplantation
KW - Vascular endothelial growth factor
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U2 - 10.1097/TP.0b013e31817c6f63
DO - 10.1097/TP.0b013e31817c6f63
M3 - Article
C2 - 18580478
AN - SCOPUS:49149130917
VL - 85
SP - 1833
EP - 1840
JO - Transplantation
JF - Transplantation
SN - 0041-1337
IS - 12
ER -