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

Fenfen Peng,Hongyu Li,Shuting Li,Yuxian Wang,Wenting Liu,Wangqiu Gong,Bohui Yin,Sijia Chen,Ying Zhang,Congwei Luo,Weidong Zhou,Yihua Chen,Peilin Li,Qianyin Huang,Zhaozhong Xu,Haibo Long

doi:10.1038/s41374-019-0245-6

Abstract

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.

Highlights

Micheliolide (MCL) and parthenolide (PTL) are compounds isolated from the herbs Michelia compressa and MicheliaThese authors contributed : Fenfen Peng, Hongyu Li, Shuting LiOur previous studies on MCL showed its antiinflammatory effect on adipohepatic damage in diabetic mice [8] and the alleviation of advanced oxidation protein product (AOPP)-induced injury on mesangial cells and podocytes [9]
Studies focusing on Mtdh to date have shown that it is a multi-functional factor involved in many important processes, including cell proliferation, apoptosis, autophagy, migration, invasion, metastasis and chemotherapy resistance, via activating signalling pathways such as NF-κB, PI3K/AKT and MAPK [19, 21,22,23,24]
We found a relationship between Mtdh expression and dimethylamino Michael adduct of MCL (DMAMCL)/MCL treatment in two mouse renal fibrosis models, and Mtdh might be involved in the pro-fibrotic process

Summary

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Micheliolide (MCL) and parthenolide (PTL) are compounds isolated from the herbs Michelia compressa and Michelia. Renal fibrosis is the most common feature of chronic kidney diseases (CKD) progressing to end-stage renal disease. This process involves the loss of the renal parenchyma and the excessive accumulation of extracellular matrix (ECM) [10, 11]. Studies focusing on Mtdh to date have shown that it is a multi-functional factor involved in many important processes, including cell proliferation, apoptosis, autophagy, migration, invasion, metastasis and chemotherapy resistance, via activating signalling pathways such as NF-κB, PI3K/AKT and MAPK [19, 21,22,23,24]. We highlight the therapeutic efficacy of MCL on renal fibrosis in vivo and in vitro and further investigate the underlying mechanism of Mtdh as a target of MCL in this condition

Materials and methods

Discussion

Findings

Compliance with ethical standards