Lack of an apparent role for endothelin-1 in the prolonged reduction in renal perfusion following severe unilateral ischemia-reperfusion injury in the mouse.
Lack of an apparent role for endothelin-1 in the prolonged reduction in renal perfusion following severe unilateral ischemia-reperfusion injury in the mouse.
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DOI：
10.14814/phy2.13027
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发表时间：
2016-11
影响因子：
2.5
通讯作者：
Boesen EI
中科院分区：
文献类型：
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作者：
Boesen EI
目前缺乏阻断急性肾损伤进展为慢性肾病的治疗方法。内皮素-1（ET-1）是一种强有力的血管收缩剂，由缺氧诱导，先前与肾缺血再灌注（IR）损伤有关。本研究检验了以下假设：通过内皮素ETA受体阻断（ABT-627）或血管内皮细胞ET-1缺失（VEET KO）减弱ET-1的血管影响，将改善小鼠严重缺血性损伤（45分钟单侧肾缺血）后肾灌注的恢复和损伤的修复。在手术前2天开始接受溶剂或ABT-627的雄性C57 Bl/6小鼠，以及VEET KO小鼠和野生型同窝小鼠（WT）接受45分钟单侧肾IR手术，随后恢复28天。在手术前后通过脉冲多普勒超声测量肾血流速度。术前两组间肾血流速度无显著差异。在所有组中，单侧IR在术后24小时诱导IR肾脏的肾血流速度显著降低，在IR后28天部分恢复但仍低于基线。尽管对肾血流速度没有影响，但ETA受体阻断剂显著减弱了IR后肾脏的萎缩，而内皮ET-1表达缺乏对这一点没有显著影响。这些数据表明，尽管阻断ETA受体对严重缺血性损伤后的肾脏质量保护略有益处，但这种保护作用似乎并不涉及改善肾脏灌注的恢复。
Therapeutic approaches to block the progression from acute kidney injury to chronic kidney disease are currently lacking. Endothelin‐1 (ET‐1) is a powerful vasoconstrictor, induced by hypoxia, and previously implicated in renal ischemia‐reperfusion (IR) injury. This study tested the hypothesis that blunting the vascular influence of ET‐1, either through endothelin ETA receptor blockade (ABT‐627) or vascular endothelial cell deletion of ET‐1 (VEET KO), would improve recovery of renal perfusion and repair of injury following a severe ischemic insult in mice (45 min unilateral renal ischemia). Male C57Bl/6 mice receiving vehicle or ABT‐627 commencing 2 days prior to surgery, and VEET KO mice and wild‐type littermates (WT) underwent 45 min unilateral renal IR surgery followed by 28 days recovery. Renal blood velocity was measured by pulsed‐wave Doppler ultrasound before and after surgery. Renal blood velocity was not significantly different between pairs of groups before surgery. Unilateral IR induced a marked reduction in renal blood velocity of the IR kidney at 24 h postsurgery in all groups, which partially recovered but remained below baseline at 28 days post‐IR. Despite the lack of effect on renal blood velocity, ETA receptor blockade significantly attenuated the atrophy of the post‐IR kidney, whereas this was not significantly affected by lack of endothelial ET‐1 expression. These data suggest that although blockade of the ETA receptor is mildly beneficial in preserving renal mass following a severe ischemic insult, this protective effect does not appear to involve improved recovery of renal perfusion.