Lin Chen1, Gang Cao2, Ming Wang1, Ya-Long Feng1, Dan-Qian Chen1, Nosratola D Vaziri3, Shougang Zhuang4, Ying-Yong Zhao1. 1. School of Pharmacy, Faculty of Life Science & Medicine, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi, 710069, China. 2. School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang, 310053, China. 3. Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, CA, 92897, USA. 4. Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai, 200120, China.
Abstract
SCOPE: Fibrosis plays a key role in the progression of various diseases. Matrix metalloproteinases (MMPs) are important for epithelial-mesenchymal transition (EMT), which contributes to organ fibrosis. Four new poricoic acids are identified, poricoic acid ZI, ZJ, ZK, and ZL, as novel MMP inhibitors from edible mushroom Poria cocos. METHODS: Molecular docking, siRNA techniques, TGF-β1-treated renal cells, and unilateral ureteral obstructed (UUO) mice are used to explore the potential efficacy of the novel MMP inhibitors in mitigating the fibrotic process. RESULTS: Treatment with four poricoic acids downregulates profibrotic protein expression in TGF-β1-induced HK-2 cells. Similar results are observed in NRK-52E and NRK-49F cells, indicating that poricoic acids can suppress EMT. Furthermore, both in vitro and in vivo experiments demonstrate that poricoic acid ZI (PZI) exerts a stronger inhibitory effect on protein expression and enzymatic activity of MMP-13 than the other three compounds, which is consistent with the docking results. The inhibitory effect of PZI on MMP-13 is partially attenuated by MMP-13 RNAi in HK-2 cells and UUO mice. CONCLUSIONS: The findings indicate that as a specific MMP-13 inhibitor, PZI attenuates EMT and renal fibrosis. Therefore, the MMP-13 inhibitor PZI can be a novel therapeutic candidate for limiting EMT and renal fibrosis.
SCOPE: Fibrosis plays a key role in the progression of various diseases. Matrix metalloproteinases (MMPs) are important for epithelial-mesenchymal transition (EMT), which contributes to organ fibrosis. Four new poricoic acids are identified, poricoic acid ZI, ZJ, ZK, and ZL, as novel MMP inhibitors from edible mushroomPoria cocos. METHODS: Molecular docking, siRNA techniques, TGF-β1-treated renal cells, and unilateral ureteral obstructed (UUO) mice are used to explore the potential efficacy of the novel MMP inhibitors in mitigating the fibrotic process. RESULTS: Treatment with four poricoic acids downregulates profibrotic protein expression in TGF-β1-induced HK-2 cells. Similar results are observed in NRK-52E and NRK-49F cells, indicating that poricoic acids can suppress EMT. Furthermore, both in vitro and in vivo experiments demonstrate that poricoic acid ZI (PZI) exerts a stronger inhibitory effect on protein expression and enzymatic activity of MMP-13 than the other three compounds, which is consistent with the docking results. The inhibitory effect of PZI on MMP-13 is partially attenuated by MMP-13 RNAi in HK-2 cells and UUO mice. CONCLUSIONS: The findings indicate that as a specific MMP-13 inhibitor, PZI attenuates EMT and renal fibrosis. Therefore, the MMP-13 inhibitor PZI can be a novel therapeutic candidate for limiting EMT and renal fibrosis.
Authors: Ya-Long Feng; Gang Cao; Dan-Qian Chen; Nosratola D Vaziri; Lin Chen; Jun Zhang; Ming Wang; Yan Guo; Ying-Yong Zhao Journal: Cell Mol Life Sci Date: 2019-05-30 Impact factor: 9.261