Celastrol alleviates renal fibrosis by upregulating cannabinoid receptor 2 expression.
Celastrol alleviates renal fibrosis by upregulating cannabinoid receptor 2 expression.
复制标题
雷公藤红素通过上调大麻素受体 2 表达减轻肾纤维化
DOI：
10.1038/s41419-018-0666-y
复制
发表时间：
2018-05-22
影响因子：
9
通讯作者：
Zhang KQ
中科院分区：
文献类型：
--
作者：
Tang M;Cao X;Zhang K;Li Y;Zheng QY;Li GQ;He QH;Li SJ;Xu GL;Zhang KQ
肾纤维化是各种慢性肾脏疾病的最终表现，目前尚无有效的治疗方法可以预防或逆转它。雷公藤红素是一种源自中药的三萜类化合物，是一种已知的有效抗纤维化剂。然而，雷公藤红素抗肾纤维化的潜在作用机制仍不清楚。在这项研究中，我们发现雷公藤红素治疗显着减轻单侧输尿管梗阻（UUO）引起的小鼠肾纤维化。肾小管损伤的显着减少就证明了这一点；胶原沉积；纤连蛋白、I 型胶原蛋白和 α-平滑肌肌动蛋白的积累；促纤维化因子Vim、Cola1和TGF-β1mRNA的表达水平以及炎症反应。雷公藤红素在叶酸诱导的小鼠肾纤维化模型中显示出类似的作用。此外，雷公藤红素增强了小鼠纤维化肾组织和转化生长因子 β1 (TGF-β1) 刺激的人肾 2 (HK-2) 细胞中抗纤维化因子大麻素受体 2 (CB2R) 的表达。此外，CB2R 拮抗剂 (SR144528) 消除了雷公藤红醇介导的对肾纤维化的有益作用。此外，雷公藤红素显着抑制 UUO 或 TGF-β1 诱导的促纤维化因子 SMAD 家族成员 3 (Smad3) 的激活。通过抑制剂 (SIS3) 抑制 Smad3 激活可显着减少 TGF-β1 诱导的 CB2R 表达下调。总之，我们的研究提供了第一个直接证据，证明雷公藤红素通过抑制 Smad3 信号通路激活上调 CB2R 表达，从而显着减轻肾纤维化。因此，雷公藤红素可能成为治疗肾纤维化患者的潜在药物。
Renal fibrosis is the final manifestation of various chronic kidney diseases, and no effective therapy is available to prevent or reverse it. Celastrol, a triterpene that derived from traditional Chinese medicine, is a known potent anti-fibrotic agent. However, the underlying mechanisms of action of celastrol on renal fibrosis remain unknown. In this study, we found that celastrol treatment remarkably attenuated unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis. This was evidenced by the significant reduction in tubular injury; collagen deposition; accumulation of fibronectin, collagen I, and α-smooth muscle actin; and the expression levels of pro-fibrotic factorsVim,Cola1, andTGF-β1mRNA, as well as inflammatory responses. Celastrol showed similar effects in a folic acid-induced mouse renal fibrosis model. Furthermore, celastrol potentiated the expression of the anti-fibrotic factor cannabinoid receptor 2 (CB2R) in established mouse fibrotic kidney tissues and transforming growth factor β1 (TGF-β1)-stimulated human kidney 2 (HK-2) cells. In addition, the CB2R antagonist (SR144528) abolished celastrol-mediated beneficial effects on renal fibrosis. Moreover, UUO- or TGF-β1-induced activation of the pro-fibrotic factor SMAD family member 3 (Smad3) was markedly inhibited by celastrol. Inhibition of Smad3 activation by an inhibitor (SIS3) markedly reduced TGF-β1-induced downregulation of CB2R expression. In conclusion, our study provides the first direct evidence that celastrol significantly alleviated renal fibrosis, by contributing to the upregulation of CB2R expression through inhibiting Smad3 signaling pathway activation. Therefore, celastrol could be a potential drug for treating patients with renal fibrosis.
登录
查看更多内容
影响因子：
7.4
作者：
Mukhopadhyay, Partha;Rajesh, Mohanraj;Pan, Hao;Patel, Vivek;Mukhopadhyay, Bani;Batkai, Sandor;Gao, Bin;Hasko, Gyoergy;Pacher, Pal
通讯作者：
Pacher, Pal
影响因子：
7.7
作者：
Barutta F;Piscitelli F;Pinach S;Bruno G;Gambino R;Rastaldi MP;Salvidio G;Di Marzo V;Cavallo Perin P;Gruden G
通讯作者：
Gruden G
DOI：
10.3390/molecules20011277
发表时间：
2015-01-14
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Lee PJ;Woo SJ;Jee JG;Sung SH;Kim HP
通讯作者：
Kim HP
雷公藤红素诱导的 MiR-21/ERK 信号通路抑制可减轻心脏纤维化和功能障碍
影响因子：
--
作者：
Cheng, Mian;Wu, Gang;Zhang, Cuntai
通讯作者：
Zhang, Cuntai
影响因子：
7.5
作者：
Choi HY;Lee HG;Kim BS;Ahn SH;Jung A;Lee M;Lee JE;Kim HJ;Ha SK;Park HC
通讯作者：
Park HC