Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury.
Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury.
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DOI：
10.1038/ki.2015.176
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发表时间：
2015-10
影响因子：
19.6
通讯作者：
Liang M
中科院分区：
文献类型：
--
作者：
Wang F;Zhang G;Lu Z;Geurts AM;Usa K;Jacob HJ;Cowley AW;Wang N;Liang M
由SerpinC 1编码的抗凝血酶III是体内主要的抗凝分子，具有抗炎作用。我们发现，抗凝血酶III活性低的患者在心脏手术后发生急性肾损伤的风险更高。为了进一步研究这一点，我们产生SerpinC 1杂合敲除大鼠，并在中度肾缺血/再灌注损伤模型中观察急性肾损伤的发展。与野生型同窝仔相比，SerpinC 1 +/−大鼠的肾损伤（通过再灌注24小时后的血清肌酐和肾小管损伤评分评估）显著加重。与此同时，SerpinC 1 +/−大鼠的肾脏氧化应激、肾小管凋亡和巨噬细胞浸润在这种损伤后显著加重。然而，在任何一组大鼠的肾脏中均未发现显著的血栓形成。据报道，抗凝血酶III除了具有抗炎作用和防止肾衰竭之外，还刺激前列腺素I2的产生，前列腺素I2是肾皮质血流的已知调节剂。再灌注后3 h，野生型大鼠肾脏中前列腺素F1α（前列腺素I2的可测定代谢产物）增加。SerpinC 1 +/−大鼠中前列腺素F1α的增加显著减弱，这发生在肾小管损伤和氧化应激增加之前。因此，我们的研究发现SerpinC 1不足在增加肾缺血/再灌注损伤的严重程度中的新作用。
Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1+/− rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1+/− rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1α, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1α was significantly blunted in SerpinC1+/− rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury.