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Blocking 5-LO pathway alleviates renal fibrosis by inhibiting the epithelial-mesenchymal transition
- Source :
- Biomedicine & Pharmacotherapy, Vol 138, Iss, Pp 111470-(2021)
- Publication Year :
- 2021
- Publisher :
- Elsevier, 2021.
-
Abstract
- 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.
- Subjects :
- Male
0301 basic medicine
Leukotrienes
Epithelial-Mesenchymal Transition
5-Lipoxygenase-Activating Proteins
Vimentin
Inflammation
RM1-950
urologic and male genital diseases
Mice
03 medical and health sciences
0302 clinical medicine
Fibrosis
Renal fibrosis
Zileuton
medicine
Animals
Humans
Epithelial–mesenchymal transition
Cells, Cultured
Mice, Knockout
Pharmacology
5-Lipoxygenase
Kidney
biology
business.industry
urogenital system
General Medicine
medicine.disease
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
5-Lipoxygenase-Activating Protein Inhibitors
030220 oncology & carcinogenesis
Arachidonate 5-lipoxygenase
biology.protein
Cancer research
Female
Kidney Diseases
Therapeutics. Pharmacology
medicine.symptom
business
Epithelial mesenchymal transition
Signal Transduction
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 07533322
- Volume :
- 138
- Database :
- OpenAIRE
- Journal :
- Biomedicine & Pharmacotherapy
- Accession number :
- edsair.doi.dedup.....f0fdcd5fe060be5dc1aca8acd26418f0