Inhibition of mTORC1 signaling protects kidney from irradiation-induced toxicity via accelerating recovery of renal stem-like cells.
Inhibition of mTORC1 signaling protects kidney from irradiation-induced toxicity via accelerating recovery of renal stem-like cells.
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抑制 mTORC1 信号传导可通过加速肾干细胞样细胞的恢复来保护肾脏免受辐射诱导的毒性
DOI：
10.1186/s13287-018-0963-5
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发表时间：
2018-08-14
影响因子：
7.5
通讯作者：
Zeng H
中科院分区：
文献类型：
--
作者：
Shao L;Yang W;Xu R;Zhu S;Huang Y;Li H;Wu X;Yue M;Xiong X;Chen X;Kuang B;Fan G;Zhu Q;Zeng H
在放射治疗实践中，辐射诱导的肾损伤不可避免，这限制了肿瘤治疗的有效放疗剂量。在本研究中，对雷帕霉素靶蛋白复合物1（mTORC1）信号通路在辐射诱导的肾损伤中的作用进行了研究。
小鼠接受8.0戈瑞的全身X射线照射，随后用雷帕霉素进行治疗。通过苏木精 - 伊红染色评估肾脏形态的变化。通过免疫染色检测pS6和CD133的表达。通过TUNEL、半胱天冬酶 - 3和BrdU染色测量细胞凋亡和增殖。通过蛋白质印迹分析确定mTORC1、转化生长因子 - β（TGF - β）和核因子 - κB（NF - κB）信号通路的激活情况。
我们的数据显示，辐射破坏了肾小体和肾小管的结构，降低了CD133⁺肾干细胞样细胞的密度，这与照射后细胞凋亡增加和细胞增殖减少有关。在受照射的肾组织中检测到mTORC1、TGF - β和NF - κB信号通路被激活，而雷帕霉素治疗可抑制这些通路。照射后应用雷帕霉素可减少肾组织中的细胞凋亡，增加自噬和细胞增殖。雷帕霉素治疗后，受照射肾脏中CD133⁺肾干细胞样细胞的密度显著增加。经雷帕霉素治疗后，受照射的肾小体和肾小管的形态逐渐恢复。
这些发现表明，雷帕霉素抑制mTORC1信号通路可通过减少细胞凋亡和增加CD133⁺肾干细胞样细胞来减轻辐射诱导的肾毒性。
本文的网络版（10.1186/s13287 - 018 - 0963 - 5）包含补充材料，授权用户可获取。
BackgroundIrradiation-induced kidney damage is inevitable during radiotherapeutic practice, which limits effective radiotherapy doses on tumor treatment. In the present study, the role of mTOR complex 1 (mTORC1) signaling was investigated in irradiation-induced renal injuries.MethodsMice were exposed to 8.0-Gy X-ray of total body irradiation and subsequently treated with rapamycin. Changes of renal morphology were assessed by hematoxylin and eosin staining. Expression of pS6 and CD133 was detected via immunostaining. Cellular apoptosis and proliferation were measured by TUNEL, caspase-3 and BrdU staining. Activation of mTORC1, TGF-β and NF-κB signaling pathways was determined through western blot analysis.ResultsOur data displayed that irradiation disrupted the structures of renal corpuscles and tubules and decreased the density of CD133+renal stem-like cells, which were related with increasing cellular apoptosis and decreasing cell proliferation post exposure. Activation of mTORC1, TGF-β and NF-κB signaling pathways was determined in irradiated renal tissues, which were inhibited by rapamycin treatment. Application of rapamycin after irradiation decreased cellular apoptosis and increased autophagy and cell proliferation in renal tissues. The density of CD133+renal stem-like cells was significantly increased in irradiated kidneys after rapamycin treatment. The morphology of irradiated renal corpuscles and tubules was gradually recovered upon rapamycin treatment.ConclusionsThese findings indicate that inhibition of mTORC1 signaling by rapamycin ameliorates irradiation-induced renal toxicity mediated by decreasing cellular apoptosis and increasing CD133+renal stem-like cells.
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影响因子：
16.6
作者：
Leibowitz, Brian J.;Wei, Liang;Zhang, Lin;Ping, Xiaochun;Epperly, Michael;Greenberger, Joel;Cheng, Tao;Yu, Jian
通讯作者：
Yu, Jian
影响因子：
3.8
作者：
Lopez-Gaitan J;Ebert MA;Robins P;Boucek J;Leong T;Willis D;Bydder S;Podias P;Waters G;O'Mara B;Chu J;Faggian J;Williams L;Hofman MS;Spry NA
通讯作者：
Spry NA
DOI：
10.1186/1748-717x-8-207
发表时间：
2013-09-05
期刊：
Radiation oncology (London, England)
影响因子：
--
作者：
Nour AA;Alaradi A;Mohamed A;Altuwaijri S;Rudat V
通讯作者：
Rudat V
TGFβ和PDGF信号传导的结合抑制减弱了辐射诱导的肺纤维化。
影响因子：
7.2
作者：
Dadrich M;Nicolay NH;Flechsig P;Bickelhaupt S;Hoeltgen L;Roeder F;Hauser K;Tietz A;Jenne J;Lopez R;Roehrich M;Wirkner U;Lahn M;Huber PE
通讯作者：
Huber PE
DOI：
10.1016/j.ijrobp.2016.07.026
发表时间：
2016-11-15
影响因子：
7
作者：
Chung, Eun Joo;Sowers, Anastasia;Thetford, Angela;McKay-Corkum, Grace;Chung, Su I.;Mitchell, James B.;Citrin, Deborah E.
通讯作者：
Citrin, Deborah E.