Sialic Acid Rescues Repurified Lipopolysaccharide-Induced Acute Renal Failure via Inhibiting TLR4/PKC/gp91-Mediated Endoplasmic Reticulum Stress, Apoptosis, Autophagy, and Pyroptosis Signaling
Sialic Acid Rescues Repurified Lipopolysaccharide-Induced Acute Renal Failure via Inhibiting TLR4/PKC/gp91-Mediated Endoplasmic Reticulum Stress, Apoptosis, Autophagy, and Pyroptosis Signaling
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DOI：
10.1093/toxsci/kfu121
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发表时间：
2014-09-01
影响因子：
3.8
通讯作者：
Chien, Chiang-Ting
中科院分区：
文献类型：
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作者：
Yang, Chih-Ching;Yao, Chien-An;Chien, Chiang-Ting
脂多糖（LPS）通过Toll样受体2（TLR 2）和Toll样受体4（TLR 4）活化诱导全身性炎症，其中氧化损伤在多器官衰竭中起关键作用。由于唾液酸（SA）能中和LPS的毒性，我们研究了SA对再纯化LPS（rLPS）诱发的急性肾功能衰竭的作用及其机制。我们通过评价血液和肾脏活性氧（ROS）反应、肾脏和全身血流动力学、肾功能、组织病理学和分子机制，评估了静脉注射SA（10 mg/kg体重）对雌性Wistar大鼠rLPS诱导的肾损伤的影响。SA可以通过高结合亲和力与rLPS相互作用。rLPS剂量和时间依赖性地降低大鼠动脉血压、肾微循环和血流量，并增加血管阻力。rLPS通过触发肾脏中p-IRE 1 α/p-JNK/CHOP/GRP 78/ATF 4介导的内质网（ER）应激、Bax/PARP介导的凋亡、Beclin-1/Atg 5-Atg 12/LC 3-II介导的自噬和caspase 1/IL-1 β介导的焦亡来增强单核细胞/巨噬细胞（艾德-1）浸润和ROS产生并损害肾脏。在rLPS刺激后30 min，而不是60 min，SA处理，gp 91 siRNA和蛋白激酶C-α（PKC）抑制剂通过抑制TLR 4/PKC/NADPH氧化酶gp 91介导的ER应激、细胞凋亡、自噬和肾近端小管细胞和大鼠肾脏中的焦亡，有效地挽救了rLPS诱导的急性肾衰竭。在对rLPS或IFN γ的应答中，Atg 5 siRNA可以抑制Atg 5、FADD、LC 3-II和PARP表达的增强。白蛋白（10 mg/kg体重）不能挽救rLPS诱导的损伤。总之，SA的早期治疗（30分钟内）通过降低LPS毒性和随后抑制rLPS激活的TLR 4/PKC/gp 91/ER应激/凋亡/自噬/焦亡信号传导来减弱rLPS诱导的肾衰竭。
Lipopolysaccharides (LPS) through Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) activation induce systemic inflammation where oxidative damage plays a key role in multiple organ failure. Because of the neutralization of LPS toxicity by sialic acid (SA), we determined its effect and mechanisms on repurified LPS (rLPS)-evoked acute renal failure. We assessed the effect of intravenous SA (10 mg/kg body weight) on rLPS-induced renal injury in female Wistar rats by evaluating blood and kidney reactive oxygen species (ROS) responses, renal and systemic hemodynamics, renal function, histopathology, and molecular mechanisms. SA can interact with rLPS through a high binding affinity. rLPS dose-and time-dependently reduced arterial blood pressure, renal microcirculation and blood flow, and increased vascular resistance in the rats. rLPS enhanced monocyte/macrophage (ED-1) infiltration and ROS production and impaired kidneys by triggering p-IRE1 alpha/p-JNK/CHOP/GRP78/ATF4-mediated endoplasmic reticulum (ER) stress, Bax/PARP-mediated apoptosis, Beclin-1/Atg5-Atg12/LC3-II-mediated autophagy, and caspase 1/IL-1 beta-mediated pyroptosis in the kidneys. SA treatment at 30 min, but not 60 min after rLPS stimulation, gp91 siRNA and protein kinase C-alpha (PKC) inhibitor efficiently rescued rLPS-induced acute renal failure via inhibition of TLR4/PKC/NADPH oxidase gp91-mediated ER stress, apoptosis, autophagy and pyroptosis in renal proximal tubular cells, and rat kidneys. In response to rLPS or IFN gamma, the enhanced Atg5, FADD, LC3-II, and PARP expression can be inhibited by Atg5 siRNA. Albumin (10 mg/kg body weight) did not rescue rLPS-induced injury. In conclusion, early treatment (within 30 min) of SA attenuates rLPS-induced renal failure via the reduction in LPS toxicity and subsequently inhibiting rLPS-activated TLR4/PKC/gp91/ER stress/apoptosis/autophagy/pyroptosis signaling.