1. Fluorofenidone attenuates interleukin-1β production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction.
- Author
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Zheng L, Zhang J, Yuan X, Tang J, Qiu S, Peng Z, Yuan Q, Xie Y, Mei W, Tang Y, Meng J, Hu G, and Tao L
- Subjects
- Animals, CARD Signaling Adaptor Proteins metabolism, Caspase 1 metabolism, Chemotaxis, Leukocyte drug effects, Disease Models, Animal, Down-Regulation, Fibrosis, HEK293 Cells, Humans, Inflammasomes genetics, Inflammasomes immunology, Inflammasomes metabolism, Interleukin-1beta genetics, Kidney immunology, Kidney metabolism, Kidney pathology, Male, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Nephritis immunology, Nephritis metabolism, Nephritis pathology, Rats, Sprague-Dawley, Signal Transduction drug effects, Time Factors, Ureteral Obstruction immunology, Ureteral Obstruction metabolism, Ureteral Obstruction pathology, Anti-Inflammatory Agents pharmacology, Inflammasomes drug effects, Interleukin-1beta metabolism, Kidney drug effects, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Nephritis prevention & control, Pyridones pharmacology, Ureteral Obstruction drug therapy
- Abstract
Aim: We explored whether Fluorofenidone reduced interleukin-1β (IL-1β) production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction (UUO)., Methods: Ureteral obstruction rats were treated with Fluorofenidone (500 mg/kg per day) for 3, 7 days. Morphologic analysis and leukocytes infiltration were assessed in ligated kidneys. Furthermore, plasmids of NLRP3, ASC, pro-Caspase-1, pro-IL-1β were co-transfected into 293 T cells, and then treated with Fluorofenidone (2 mM). The expression of NLRP3, ASC, pro-caspase-1, cleavage caspase-1, pro-IL-1β and cleavage IL-1β were measured by Western blot or real-time PCR in vivo and in vitro. Moreover the interaction of NLRP3 inflammasome-assembly was detected by co-immunoprecipitation and confocal immunofluorescence., Results: Fluorofenidone treatment significantly attenuated renal fibrosis and leukocytes infiltration in UUO model. Fluorofenidone had no effect on the expression of pro-IL-1β. Interestingly, Fluorofenidone inhibited the activation of NLRP3 inflammasome, downregulated Caspase-1 levels and thereby decreased the cleavage of pro-IL-1β into IL-1β in vivo and in vitro. Fluorofenidone treatment distinctively weakened the interaction between NLRP3 and ASC, as well as ASC and pro-Caspase-1 in vivo. However, Fluorofenidone treatment only significantly weakened the interaction between ASC and pro-Caspase-1 in co-transfected 293 T cells., Conclusion: Fluorofenidone serves as a novel anti-inflammatory agent that attenuates IL-1β production in UUO model by interacting with NLRP3 inflammasome., (© 2017 Asian Pacific Society of Nephrology.)
- Published
- 2018
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