Interleukin-6 mediates angiotensinogen gene expression during liver regeneration.
Interleukin-6 mediates angiotensinogen gene expression during liver regeneration.
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DOI：
10.1371/journal.pone.0067868
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lee PH
中科院分区：
文献类型：
--
作者：
Lai HS;Lin WH;Lai SL;Lin HY;Hsu WM;Chou CH;Lee PH
血管紧张素原是血管紧张素Ⅱ的前体，与缺血再灌注损伤有关。血管紧张素II减少肝切除后的肝再生，并导致缩小体积的肝移植的功能障碍和失败。然而，血管紧张素原在肝脏再生过程中的调节仍不清楚。探讨血管紧张素原在肝再生过程中的调节作用，以预防肝再生过程中血管紧张素II相关的缺血再灌注损伤。采用小鼠体外肝部分切除动物模型，观察肝再生过程中白细胞介素6(IL-6)和血管紧张素原的表达。采用酶免疫分析法(EIA)检测血清IL-6和血管紧张素原水平。逆转录-聚合酶链式反应检测血管紧张素原mRNA。免疫印迹法检测组织中血管紧张素原蛋白的表达。采用原代培养的小鼠肝细胞，研究IL-6诱导血管紧张素原的作用。化学抑制剂被用来干扰信号转导通路。合成的双链寡核苷酸(ODN)被用作“诱饵”顺式元件来研究转录。Ki-67染色和定量检测肝再生情况。在体内模型中，血清IL-6水平与血管紧张素原水平相关。在体外模型中，IL-6转录调控血管紧张素原的表达。此外，IL-6通过Janus激酶(JAK)/信号转导和转录激活因子3(STAT3)和JAK/p38信号通路介导血管紧张素原的表达。诱骗ODN分析表明，STAT3和核因子-kB(NF-kB)在IL-6对血管紧张素原的转录调控中也起着关键作用。IL-6介导的信号、JAK2、STAT3和p38抑制剂降低了部分肝切除小鼠血管紧张素原的表达。在肝再生过程中，IL-6促进血管紧张素原的表达依赖于JAK/STAT3和JAK/p38/NF-kB信号通路。阻断血管紧张素原调节的分子机制可作为预防肝再生过程中血管紧张素II相关的缺血再灌注损伤的治疗策略的基础。
Angiotensinogen is the precursor of angiotensin II, which is associated with ischemia-reperfusion injury. Angiotensin II reduces liver regeneration after hepatectomy and causes dysfunction and failure of reduced-size liver transplants. However, the regulation of angiotensinogen during liver regeneration is still unclear. To investigate the regulation of angiotensinogen during liver regeneration for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration. A mouse in vitro partial hepatectomy animal model was used to evaluate the expression of interleukin-6 (IL-6) and angiotensinogen during liver regeneration. Serum IL-6 and angiotensinogen were detected by enzyme immunoassay (EIA). Angiotensinogen mRNA was detected by RT-PCR. Tissue levels of angiotensinogen protein were detected by Western blot analysis. Primary cultures of mouse hepatocytes were used to investigate IL-6-induced angiotensinogen. Chemical inhibitors were used to perturb signal transduction pathways. Synthetic double-stranded oligodeoxynucleotides (ODNs) were used as ‘decoy’ cis-elements to investigate transcription. Ki 67 staining and quantification were used to verify liver regeneration. In the in vivo model, the levels of serum IL-6 and angiotensinogen correlated. In the in vitro model, IL-6 transcriptionally regulated angiotensinogen expression. Additionally, IL-6 mediated angiotensinogen expression through the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and JAK/p38 signaling. Decoy ODN analyses revealed that STAT3 and nuclear factor-kB (NF-kB) also played critical roles in the transcriptional regulation of angiotensinogen by IL-6. IL-6-mediated signaling, JAK2, STAT3 and p38 inhibitors reduced angiotensinogen expression in the partially hepatectomized mice. During liver regeneration, IL-6-enhanced angiotensinogen expression is dependent on the JAK/STAT3 and JAK/p38/NF-kB signaling pathways. Interruption of the molecular mechanisms of angiotensinogen regulation may be applied as the basis of therapeutic strategies for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.
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