Blocking 5-LO pathway alleviates renal fibrosis by inhibiting the epithelial-mesenchymal transition

• Published in: Biomedicine & pharmacotherapy 2021-06, Vol.138, p.111470, Article 111470
• Main Authors: Zhou, Jian, Li, Rui, Liu, Qinhui, Zhang, Jinhang, Huang, Hui, Huang, Cuiyuan, Zhang, Guorong, Zhao, Yingnan, Wu, Tong, Tang, Qin, Huang, Ya, Zhang, Zijing, Li, Yanping, He, Jinhan
• Format: Article
• Language: English
• Subjects: 5-Lipoxygenase; 5-Lipoxygenase-Activating Protein Inhibitors - pharmacology; 5-Lipoxygenase-Activating Proteins - genetics; 5-Lipoxygenase-Activating Proteins - metabolism; Animals; Cells, Cultured; Epithelial mesenchymal transition; Epithelial-Mesenchymal Transition - physiology; Female; Fibrosis; Humans; Kidney Diseases - genetics; Kidney Diseases - metabolism; Leukotrienes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Renal fibrosis; Signal Transduction - physiology; Zileuton
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2021.111470

The enzyme 5-lipoxygenase (5-LO) converts arachidonic acid to leukotrienes, which mediate inflammation. The enzyme is known to contribute to organ fibrosis, but how it contributes to renal fibrosis is unclear. Here, we reported that fibrotic kidneys expressed high levels of 5-LO, and deleting the 5-LO gene mitigated renal fibrosis in mice subjected to unilateral ureteral obstruction (UUO), based on assays of collagen deposition, injury and inflammation. Mechanistically, the exogenous leukotrienes B4 and C4, the downstream products of 5-LO, could induce the epithelial-mesenchymal transition (EMT) in kidney epithelial cell cultures, based on assays of E-cadherin, vimentin and snail expression. Studies in UUO mice confirmed that 5-LO deletion inhibited the EMT in the obstructed kidney. More importantly, 5-LO inhibitor zileuton loaded in CREKA-Lip, which could target to fibrotic kidney, markedly attenuated UUO-induced renal fibrosis and injury by inhibiting the EMT in the obstructed kidney. Our results suggested that 5-LO activity may contribute to renal fibrosis by promoting renal EMT, implying that the enzyme may be a useful therapeutic target. [Display omitted] •5-LO deletion attenuated UUO-induced fibrosis, renal injury and inflammation.•Leukotrienes induced EMT in kidney cells in vitro.•5-LO inhibitor zileuton loaded in CREKA-Lip, which could target to fibrotic kidney, attenuated renal fibrosis and injury.•Deletion or inhibition of 5-LO inhibited epithelial–mesenchymal transition in obstructed kidneys.