The Matrix Metalloproteinase‐13 Inhibitor Poricoic Acid ZI Ameliorates Renal Fibrosis by Mitigating Epithelial‐Mesenchymal Transition

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. Four new poricoic acids isolated from the surface layer of Poria cocos can retard renal fibrosis by regulating epithelial‐mesenchymal transition via the inhibition of matrix metalloproteinases expression in both renal epithelial cells, HK‐2 and NRK‐52E, and fibroblast cells, NRK‐49F. Further study demonstrates that PZI is a specific MMP‐13 inhibitor in EMT and renal fibrosis.