The Protective Effect of A Short Peptide Derived From Cold-Inducible RNA-Binding Protein in Renal Ischemia-Reperfusion Injury.
The Protective Effect of A Short Peptide Derived From Cold-Inducible RNA-Binding Protein in Renal Ischemia-Reperfusion Injury.
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DOI：
10.1097/shk.0000000000000988
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Wang P
中科院分区：
文献类型：
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作者：
McGinn J;Zhang F;Aziz M;Yang WL;Nicastro J;Coppa GF;Wang P
细胞外冷诱导rna结合蛋白（CIRP）具有损伤相关分子模式（DAMP）的功能，已被证明在肾缺血再灌注（I/R）后发生的损伤中起部分作用。来自CIRP的短肽C23与toll样受体4 （TLR4）共受体髓样分化因子2 （MD2）结合。我们假设C23通过阻断CIRP减少肾缺血再灌注（RIR）损伤。我们观察到，C23预处理显著降低了重组小鼠cirp诱导的巨噬细胞中TNF-α的水平，并呈剂量依赖性。C57BL/6小鼠双侧肾蒂夹持35min诱导缺血，再灌注24h，取血和肾组织。再灌注开始时腹腔注射C23肽（8 mg/kg）或对照物。c23处理的RIR小鼠的血浆TNF-α、IL-1β和IL-6水平分别比对照小鼠降低了74%、85%和68%。c23处理小鼠肾脏中TNF-α和角质细胞化学引诱物（KC）的表达分别下降55%和60%。c23处理小鼠肾脏中肾损伤分子-1 （KIM-1）和中性粒细胞明胶酶相关脂钙素（NGAL）的表达分别显著降低46%和55%。肾组织组织学评估显示，c23治疗小鼠的损伤评分显著降低44%。最后，一项生存研究显示，C23组的存活率为70%，而载药组为37%，具有显著的生存优势。因此，C23有可能成为I/ r致肾损伤患者的一种新疗法。
Extracellular cold-inducible RNA-binding protein (CIRP) functions as damage-associated molecular pattern (DAMP) and has been demonstrated to be responsible in part for the damage occurring after renal ischemia-reperfusion (I/R). A short peptide derived from CIRP, named C23, binds to myeloid differentiation factor 2 (MD2), a Toll-like receptor 4 (TLR4) co-receptor. We hypothesize that C23 reduces renal ischemia-reperfusion (RIR) injury by blocking CIRP. We observed that pre-treatment with C23 significantly decreased the levels of recombinant mouse CIRP-induced TNF-α in a dose-dependent fashion in cultured macrophages. C57BL/6 mice were subjected to bilateral renal pedicle clamps for 35 min to induce ischemia, followed by reperfusion for 24 h and harvest of blood and renal tissue. C23 peptide (8 mg/kg) or vehicle was injected intraperitoneally at the beginning of reperfusion. Plasma TNF-α, IL-1β, and IL-6 levels were decreased in C23-treated RIR mice as compared to vehicle-treated mice by 74%, 85% and 68%, respectively. Expressions of TNF-α and keratinocyte chemoattractant (KC) in the kidneys from C23-treated mice was decreased by 55% and 60%, respectively. Expression of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in the kidney of C23-treated mice were significantly reduced by 46% and 55%, respectively. Renal tissue histological assessments revealed significant reduction in damage score by 44% in C23-treated mice. Finally, a survival study revealed a significant survival advantage with a 70% survival rate in C23 group versus 37 % in vehicle group. Thus, C23 has potential as a novel therapy for the patients suffering from I/R-induced renal injury.