The Absence of Interleukin-6 Enhanced Arsenite-Induced Renal Injury by Promoting Autophagy of Tubular Epithelial Cells with Aberrant Extracellular Signal-Regulated Kinase Activation
The Absence of Interleukin-6 Enhanced Arsenite-Induced Renal Injury by Promoting Autophagy of Tubular Epithelial Cells with Aberrant Extracellular Signal-Regulated Kinase Activation
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DOI：
10.2353/ajpath.2010.090146
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发表时间：
2010-01-01
影响因子：
6
通讯作者：
Kondo, Toshikazu
中科院分区：
文献类型：
--
作者：
Kimura, Akihiko;Ishida, Yuko;Kondo, Toshikazu
亚砷酸钠(NaAs)诱导的小鼠肾小管上皮细胞系(MProx24)表达IL-6水平升高的自噬细胞死亡(ACD)可被3-甲基腺嘌呤或ATG7基因敲除所抑制。抗IL-6抗体或JAK2抑制剂(AG490)抑制IL-6/信号转导和转录激活因子3(STAT3)信号通路，使NaAS刺激后mProx24细胞的ACD增加，从而减弱STAT3的激活，并相互促进细胞外信号调节激酶(ERK)的磷酸化。相反，ERK抑制剂PD98059可减少NaAS诱导的mProx24细胞中的ACD。BALB/c(野生型)小鼠皮下注射NaAS(12.5 mg/kg)后，肾内IL-6表达增强，主要由肾小管上皮细胞产生，并可引起以出血、急性肾小管坏死、管型形成和刷缘消失为特征的严重肾损伤，并使血清尿素氮(血尿素氮)和肌酐水平升高。此外，IL-6缺陷(IL-6(-/-))小鼠的组织病理学改变被夸大，血尿素氮和肌酐水平较高。此外，与野生型小鼠相比，经NaAS处理的IL-6(-/-)小鼠肾小管上皮细胞内ACD显著增加，STAT3活性减弱，ERK信号转导增强。最后，给野生型小鼠注射外源性IL-6显著减少了NaAS诱导的ACD和ERK的激活，最终减轻了急性肾功能障碍。因此，IL-6/STAT3信号通路可以抑制ERK的激活，这是ACD的关键步骤，最终减轻NaAS诱导的肾功能障碍。(Am J Pathol 2010,176：40-50；DOI：10.2353/ajpath.2010.090146)
Sodium arsenite (NaAs)-induced autophagic cell death (ACD) of a mouse renal tubular epithelial cell line (mProx24), which expresses enhanced levels of interleukin-6 (IL-6), was reduced by the suppression of autophagy by 3-methyladenine or Atg7 knockdown. The inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) signal pathway by anti-IL-6 antibody or a Jak2 inhibitor (AG490) exaggerated ACD of mProx24 cells after NaAs challenge, attenuating STAT3 activation and reciprocally enhancing extracellular signal-regulated kinase (ERK) phosphorylation. In contrast, an ERK inhibitor, PD98059, reduced NaAs-induced ACD in mProx24 cells. Subcutaneous injection of NaAs (12.5 mg/kg) into BALB/c (wild-type) mice enhanced intrarenal expression of IL-6, mainly produced by tubular cells, and caused severe renal injury characterized by hemorrhages, acute tubular necrosis, cast formation, and brush border disappearance, with increases in serum urea nitrogen (blood urea nitrogen) and creatinine levels. in addition, IL-6-deficient (IL-6(-/-)) mice exhibited exaggerated histopathological changes with higher blood urea nitrogen and creatinine levels. Moreover, in IL-6(-/-) mice treated with NaAs, ACD in renal tubular cells was significantly augmented, along with diminished STAT3 activation and reciprocal enhancement of ERK signaling, compared with wildtype mice. Finally, the administration of exogenous IL-6 into wild-type mice significantly reduced NaAs-induced ACD along with diminished ERK activation and eventually alleviated acute renal dysfunction. Thus, IL-6/STAT3 signal pathway could inhibit ERK activation, a crucial step for ACD, eventually attenuating NaAs-induced renal dysfunction. (Am J Pathol 2010,176:40-50; DOI: 10.2353/ajpath.2010.090146)