Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway
Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway
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Micheliolide 通过抑制 Mtdh/BMP/MAPK 通路改善肾纤维化
DOI：
10.1038/s41374-019-0245-6
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发表时间：
2019-08-01
影响因子：
5
通讯作者：
Long, Haibo
中科院分区：
文献类型：
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作者：
Peng, Fenfen;Li, Hongyu;Long, Haibo
含笑属植物（MCL），来源于小白菊（PTL），以其抗氧化和抗炎作用而闻名，在炎症性疾病和肿瘤中具有多种作用。为了研究其对肾脏疾病的作用，我们在两种肾纤维化模型-单侧输尿管闭塞（UUO）模型和缺血再灌注损伤（IRI）模型中灌胃给予DMAMCL（MCL的体内二甲基氨基Michael加成物），并在体外联合使用MCL和转化生长因子β 1（TGF-β 1）对小鼠肾小管上皮细胞（mTEC）的作用。在UUO和IRI小鼠中，DMAMCL治疗后纤维化标志物（纤连蛋白和α-SMA）的表达显著降低，而上皮标志物E-cadherin的表达恢复。MCL在TGF-β 1诱导的mTEC上皮-间质转化（EMT）中的功能与体内结果一致。Metadherin（Mtdh）在纤维化条件下被激活，表明它可能参与纤维化。有趣的是，我们发现虽然Mtdh在纤维化条件下上调，但DMAMCL/MCL可以抑制其表达。Mtdh的过表达通过调节mTECs中的BMP/MAPK通路而产生促纤维化作用，并且MCL可以特异性地逆转这种作用。总之，DMAMCL/MCL治疗通过抑制Mtdh/BMP/MAPK通路代表了肾纤维化的新的和有效的疗法。
Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for in vivo use, in two renal fibrosis models–the unilateral ureteral occlusion (UUO) model and an ischaemia-reperfusion injury (IRI) model and used MCL in combination with transforming growth factor beta 1 (TGF-β1) on mouse tubular epithelial cells (mTEC) in vitro. The expression of fibrotic markers (fibronectin and α-SMA) was remarkably reduced, while the expression of the epithelial marker E-cadherin was restored after DMAMCL treatment both in the UUO and IRI mice. MCL function in TGF-β1-induced epithelial-mesenchymal transition (EMT) in mTEC was consistent with the in vivo results. Metadherin (Mtdh) was activated in the fibrotic condition, suggesting that it might be involved in fibrogenesis. Interestingly, we found that while Mtdh was upregulated in the fibrotic condition, DMAMCL/MCL could suppress its expression. The overexpression of Mtdh exerted a pro-fibrotic effect by modulating the BMP/MAPK pathway in mTECs, and MCL could specifically reverse this effect. In conclusion, DMAMCL/MCL treatment represents a novel and effective therapy for renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.