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Updated: Nov 12, 2025
Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
Blocking 5-LO pathway alleviates renal fibrosis by inhibiting the epithelial-mesenchymal transition
Jian Zhou1, Rui Li1, Qinhui Liu2
1Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu, China; Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, China.
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.
Insights
The enzyme 5-lipoxygenase (5-LO) drives renal fibrosis by promoting epithelial-mesenchymal transition (EMT). Inhibiting 5-LO activity or targeting it with drugs like zileuton can mitigate kidney fibrosis and injury.
Area of Science:
- Nephrology
- Molecular Biology
- Inflammation Research
Background:
- 5-lipoxygenase (5-LO) is implicated in organ fibrosis, but its role in renal fibrosis remains unclear.
- Leukotrienes, downstream products of 5-LO, are known mediators of inflammation.
Purpose of the Study:
- To investigate the role of 5-lipoxygenase (5-LO) in renal fibrosis.
- To elucidate the mechanism by which 5-LO contributes to kidney fibrosis.
- To evaluate the therapeutic potential of targeting 5-LO in renal fibrosis.
Main Methods:
- Assessed 5-LO expression in fibrotic kidneys.
- Utilized gene deletion (5-LO knockout mice) and unilateral ureteral obstruction (UUO) models.
- Examined collagen deposition, inflammation, and injury markers.
- Investigated the effect of leukotrienes on kidney epithelial cells in vitro (EMT markers: E-cadherin, vimentin, snail).
- Administered 5-LO inhibitor (zileuton) encapsulated in targeted nanoparticles (CREKA-Lip) in vivo.
Main Results:
- Fibrotic kidneys showed significantly elevated 5-LO levels.
- 5-LO gene deletion attenuated renal fibrosis, injury, and inflammation in UUO mice.
- Leukotrienes B4 and C4 induced epithelial-mesenchymal transition (EMT) in kidney epithelial cells.
- 5-LO deletion inhibited EMT in obstructed kidneys.
- Targeted delivery of zileuton via CREKA-Lip markedly reduced UUO-induced renal fibrosis and injury by inhibiting EMT.
Conclusions:
- 5-lipoxygenase (5-LO) activity promotes renal fibrosis by inducing epithelial-mesenchymal transition (EMT).
- Targeting 5-LO, particularly with specific inhibitors delivered to the kidney, represents a promising therapeutic strategy for renal fibrosis.
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