Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase
Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase
复制标题
DOI：
10.1152/ajprenal.00148.2011
复制
发表时间：
2012-04-01
影响因子：
4.2
通讯作者：
Andrade, Lucia
中科院分区：
文献类型：
--
作者：
Pessoa de Souza, Ana Carolina C.;Volpini, Rildo A.;Andrade, Lucia
De Souza ACCP，Volpini RA，Shimizu MH，Sanches tr，Camara NOS，Semedo P，Rodrigues CE，Seguro AC，Andrade L.Erythropoietin通过抑制核因子-kappa B和上调内皮型一氧化氮合酶来预防脓毒症相关的急性肾损伤。Am J Physiol Renal Physiol 302：F1045-F1054,2012。2012年1月11日首次出版；DOI：10.1152/ajprenal.00148.2011。-脓毒症的病理生理学涉及复杂的细胞因子和炎症介质网络，其中核因子-kappa B激活是核心机制。内皮型一氧化氮合酶(ENOS)的下调参与了脓毒症所致的内皮功能障碍。促红细胞生成素(EPO)在应激状态下是一种主要的组织保护性细胞因子。我们利用盲肠结扎和穿孔(CLP)模型研究了EPO在脓毒症相关的急性肾损伤中的作用。Wistar大鼠分为三组：对照组(假手术组)、CLP组和CLP+EPO组。在CLP前24和1h分别给予EPO(4000IU/kg体重，ip)。另一组在给予EPO的同时给予N-硝基-L-精氨酸甲酯(L-NAME)(CLP+EPO+L-NAME)。第5组(CLP+EPOTreate)在CLP后1h和4h接受EPO治疗。术后48h，CLP+EPO组大鼠菊粉清除量显著高于CLP组和CLP+EPO+L-NAME组，红细胞压积、平均动脉压和代谢平衡无明显变化，CLP+EPOD组菊粉清除量显著高于CLP组。CLP后48h，CLP+EPO组大鼠内生肌酐清除率显著高于CLP组大鼠。在肾组织中，CLP前给予EPO可阻止脓毒症引起的巨噬细胞浸润增加，并保留eNOS表达、EPO受体(EPOR)表达、IKK-α激活、NF-kappa B激活和炎性细胞因子水平，从而提高存活率。我们的结论是，这种似乎依赖于EPOR激活和eNOS表达的保护作用，部分归因于通过下调核因子-kappa B抑制炎症反应。
de Souza ACCP, Volpini RA, Shimizu MH, Sanches TR, Camara NOS, Semedo P, Rodrigues CE, Seguro AC, Andrade L. Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting nuclear factor-kappa B and upregulating endothelial nitric oxide synthase. Am J Physiol Renal Physiol 302: F1045-F1054, 2012. First published January 11, 2012; doi:10.1152/ajprenal.00148.2011.-The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-kappa B activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLP + EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-L-arginine methyl ester (L-NAME) simultaneously with EPO administration (CLP + EPO + L-NAME). A fifth group (CLP + EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP + EPO rats presented significantly higher inulin clearance than did CLP and CLP + EPO + L-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP + EPO rats; and inulin clearance was significantly higher in CLP + EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP + EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-alpha activation, NF-kappa B activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-kappa B downregulation.