Micheliolide ameliorates renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway

• Published in: Laboratory investigation 2019-08, Vol.99 (8), p.1092-1106
• Main Authors: Peng, Fenfen, Li, Hongyu, Li, Shuting, Wang, Yuxian, Liu, Wenting, Gong, Wangqiu, Yin, Bohui, Chen, Sijia, Zhang, Ying, Luo, Congwei, Zhou, Weidong, Chen, Yihua, Li, Peilin, Huang, Qianyin, Xu, Zhaozhong, Long, Haibo
• Format: Article
• Language: English
• Subjects: 13/109; 13/44; 13/51; 38; 59; 631/154/155; 64; 64/60; 692/699/1585/104/1586; 82; 96/95; Animals; Antioxidants; Apoptosis; Bone Morphogenetic Proteins - metabolism; Cells, Cultured; Cytotoxicity; E-cadherin; Epithelial cells; Fibronectin; Fibrosis; Fibrosis - metabolism; Fibrosis - pathology; Growth factors; Hospitals; Inflammatory diseases; Ischemia; Kidney - cytology; Kidney - drug effects; Kidney - pathology; Kidney diseases; Kidney Diseases - metabolism; Kidney Diseases - pathology; Laboratory animals; Laboratory Medicine; Male; MAP kinase; MAP Kinase Signaling System - drug effects; Medical research; Medicine; Medicine & Public Health; Membrane Proteins - metabolism; Mesenchyme; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases - metabolism; Nephrology; Occlusion; Pathology; Protective Agents - pharmacology; Reperfusion; Reperfusion Injury - metabolism; RNA-Binding Proteins - metabolism; Sesquiterpenes, Guaiane - pharmacology; Transforming growth factor-b1; Tumors; Ureteral Obstruction - metabolism
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-019-0245-6

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.