Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor
Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor
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DOI：
10.1097/tp.0b013e31817c6f63
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发表时间：
2008-06-27
期刊：
影响因子：
6.2
通讯作者：
Nakao, Atsunori
中科院分区：
文献类型：
--
作者：
Faleo, Gaetano;Neto, Joao Seda;Nakao, Atsunori
背景我们先前已经证明，低浓度的一氧化碳（CO）吸入可以保护肾移植后免受冷缺血再灌注（I/R）损伤。由于血管内皮生长因子（VEGF）可促进I/R损伤时受损血管内皮细胞的恢复过程，我们研究了CO的保护作用是否涉及VEGF诱导及其上游缺氧诱导因子（HIF）-1的激活。将刘易斯大鼠肾移植物原位移植到同系受体中，所述肾移植物在威斯康星州大学在4 ℃下保存24小时。移植前和移植后24小时，受体持续保持在空气中或暴露于CO（250 ppm）中1小时。长期冷保存可导致移植肾功能进行性损害，并伴有早期炎症反应。一氧化碳显著保护移植肾免受冷I/R损伤，改善肾功能，提高受体存活率。实时逆转录-聚合酶链反应显示，早在再灌注后1小时，CO处理的肾移植物中HIF-1 α和VEGF就上调了。Western印迹显示，肾移植后1至3小时，CO显着上调VEGF表达。VEGF阳性率更高。在再灌注后3小时，在CO处理的肾移植物中主要在肾小管上皮细胞中观察到细胞，但在空气暴露的肾移植物中未观察到细胞。YC-1，HIF-1 α抑制剂，完全取消了CO对VEGF诱导的作用，并逆转了CO的保护作用。YC-1.Conclusion.这些结果表明，CO对肾冷I/R损伤的保护作用可能涉及通过其上游信号HIF-1活化上调VEGF。
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 degrees 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-1 alpha 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-1 alpha 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.