Rapamycin Upregulates Connective Tissue Growth Factor Expression in Hepatic Progenitor Cells Through TGF-β-Smad2 Dependent Signaling.
Rapamycin Upregulates Connective Tissue Growth Factor Expression in Hepatic Progenitor Cells Through TGF-β-Smad2 Dependent Signaling.
复制标题
DOI：
10.3389/fphar.2018.00877
复制
发表时间：
2018
影响因子：
5.6
通讯作者：
Chen XP
中科院分区：
文献类型：
--
作者：
Wu Y;Wang W;Peng XM;He Y;Xiong YX;Liang HF;Chu L;Zhang BX;Ding ZY;Chen XP
雷帕霉素（西罗莫司）是一种mTOR激酶抑制剂，目前被广泛用作器官移植中预防移植物排斥反应的免疫抑制药物。然而，最近的一些研究报道，它在器官纤维化的进展中具有促纤维化作用，并且其在肝纤维化中的确切作用仍然知之甚少。在这里，我们发现，雷帕霉素上调结缔组织生长因子（CTGF）在肝祖细胞（HPC）的转录水平的表达。使用慢病毒介导的小发夹RNA（shRNA），我们证明了mTOR、Raptor或Rictor的敲低模拟了雷帕霉素治疗的效果。从机制上讲，雷帕霉素抑制mTOR活性导致PI 3 K-Akt通路过度活跃，而这种激活抑制了HPC中CTGF的表达。此外，雷帕霉素激活TGF-β-Smad信号通路，TGF-β I型受体（TGF-βRI）丝氨酸/苏氨酸激酶抑制剂可完全阻断雷帕霉素对HPC的作用。此外，Smad 2通过雷帕霉素激活的TGF-β-Smad信号转导参与CTGF的诱导，因为敲低完全阻断CTGF的诱导，而Smad 4表达的敲低部分抑制诱导，而Smad 3敲低没有影响。雷帕霉素还诱导ROS产生和潜在的TGF-β活化，这有助于TGF-β-Smad信号传导。总之，本研究表明雷帕霉素上调HPC中的CTGF，并表明雷帕霉素对肝脏具有潜在的纤维化作用。
Rapamycin (sirolimus) is a mTOR kinase inhibitor and is widely used as an immunosuppressive drug to prevent graft rejection in organ transplantation currently. However, some recent investigations have reported that it had profibrotic effect in the progression of organ fibrosis, and its precise role in the liver fibrosis is still poorly understood. Here we showed that rapamycin upregulated connective tissue growth factor (CTGF) expression at the transcriptional level in hepatic progenitor cells (HPCs). Using lentivirus-mediated small hairpin RNA (shRNA) we demonstrated that knockdown of mTOR, Raptor, or Rictor mimicked the effect of rapamycin treatment. Mechanistically, inhibition of mTOR activity with rapamycin resulted in a hyperactive PI3K-Akt pathway, whereas this activation inhibited the expression of CTGF in HPCs. Besides, rapamycin activated the TGF-β-Smad signaling, and TGF-β receptor type I (TGFβRI) serine/threonine kinase inhibitors completely blocked the effects of rapamycin on HPCs. Moreover, Smad2 was involved in the induction of CTGF through rapamycin-activated TGF-β-Smad signaling as knockdown completely blocked CTGF induction, while knockdown of Smad4 expression partially inhibited induction, whereas Smad3 knockdown had no effect. Rapamycin also induced ROS generation and latent TGF-β activation which contributed to TGF-β-Smad signaling. In conclusion, this study demonstrates that rapamycin upregulates CTGF in HPCs and suggests that rapamycin has potential fibrotic effect in liver.