TLR9 Mediates Remote Liver Injury following Severe Renal Ischemia Reperfusion.
TLR9 Mediates Remote Liver Injury following Severe Renal Ischemia Reperfusion.
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DOI：
10.1371/journal.pone.0137511
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Leemans JC
中科院分区：
文献类型：
--
作者：
Bakker PJ;Scantlebery AM;Butter LM;Claessen N;Teske GJ;van der Poll T;Florquin S;Leemans JC
缺血再灌注损伤是急性肾损伤的常见原因，其特征在于肾小管损伤。线粒体DNA在严重的组织损伤时释放，并且可以通过先天免疫受体TLR 9作为损伤相关的分子模式。在这里，我们研究了TLR 9在中度或重度肾缺血再灌注损伤的背景下使用野生型C57 BL/6小鼠或TLR 9 KO小鼠的作用。中度肾缺血诱导肾功能不全，但不降低动物的幸福感，也不受TLR 9的调节。相比之下，严重的肾缺血分别在再灌注一天或五天后降低了野生型小鼠的动物健康和存活率。TLR 9缺乏改善了动物的健康和存活率。TLR 9缺乏并不减少肾脏炎症或肾小管坏死。相反，重度肾缺血诱导肝损伤，如血浆ALAT和ASAT水平升高和局灶性肝坏死所示，这可通过TLR 9缺乏预防，并与循环线粒体DNA水平和血浆LDH降低相关。我们的结论是，TLR 9不介导肾功能不全后，无论是中度或重度肾缺血。相反，我们的数据表明TLR 9是继发于缺血性急性肾损伤的肝损伤的重要介质。
Ischemia reperfusion injury is a common cause of acute kidney injury and is characterized by tubular damage. Mitochondrial DNA is released upon severe tissue injury and can act as a damage-associated molecular pattern via the innate immune receptor TLR9. Here, we investigated the role of TLR9 in the context of moderate or severe renal ischemia reperfusion injury using wild-type C57BL/6 mice or TLR9KO mice. Moderate renal ischemia induced renal dysfunction but did not decrease animal well-being and was not regulated by TLR9. In contrast, severe renal ischemia decreased animal well-being and survival in wild-type mice after respectively one or five days of reperfusion. TLR9 deficiency improved animal well-being and survival. TLR9 deficiency did not reduce renal inflammation or tubular necrosis. Rather, severe renal ischemia induced hepatic injury as seen by increased plasma ALAT and ASAT levels and focal hepatic necrosis which was prevented by TLR9 deficiency and correlated with reduced circulating mitochondrial DNA levels and plasma LDH. We conclude that TLR9 does not mediate renal dysfunction following either moderate or severe renal ischemia. In contrast, our data indicates that TLR9 is an important mediator of hepatic injury secondary to ischemic acute kidney injury.