Mefunidone ameliorates renal inflammation and tubulointerstitial fibrosis via suppression of IKKβ phosphorylation

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• 作者：Jin Zhang^a ; Linfeng Zheng^a ; Xiangning Yuan^a ; Chunyan Liu^c ; Qiongjing Yuan^a ; Feifei Xie^a ; Sisi Qiu^b ; Zhangzhe Peng^a ; Yiting Tang^d ; Jie Meng^e ; Jiao Qin^f ; Gaoyun Hu^g ; Lijian Tao^a ; ^h ; ^{taolj@csu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; ^{gucan_cs@csu.edu.cn" class="auth_mail" title="E-mail the corresponding author} (Professor)
• 关键词：Renal tubulointerstitial fibrosis ; Inflammatory response ; Macrophages ; IKKβ/IκB ; NALP3
• 刊名：International Journal of Biochemistry and Cell Biology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：80
• 期：Complete
• 页码：109-118
• 全文大小：6726 K

文摘

Mefunidone is a new pyridone agent that attenuates renal tubulointerstitial fibrosis. However, the signaling pathways involved in the effect of mefunidone on renal tubulointerstitial fibrosis have not been well explained. Inflammatory response initiates and promotes renal tubulointerstitial fibrosis, and the inhibitor of nuclear factor kappa-B kinase beta (IKKβ) is a master regulator of inflammation. This study is determined to clarify the influence of mefunidone on renal inflammation and the phosphorylation of IKKβ. Experimental renal tubulointerstitial fibrosis was induced by unilateral ureteral obstruction (UUO) for 3, 7 and 14 days in sprague dawley rat. Treatment with mefunidone was conducted simultaneously. Obstructed kidneys were harvested for the assessment. Our results showed that treatment with mefunidone ameliorated renal inflammatory injury, renal tubular lesions and interstitial fibrosis. Further studies indicated that treatment with mefunidone mitigated the expressions of tumor necrosis factorα (TNFα) and interleukin-1β (IL-1β) in the kidney. The phosphorylation of IKKβ and inhibitor of kappa-B (IκB) and the expression of NOD-like receptor family, pyrin domain containing 3 (NALP3) were also reduced in vivo after treatment with mefunidone. In vitro, peritoneal macrophages were incubated with necrotic cells or lipopolysaccharide in the presence or absence of mefunidone. Mefunidone markedly decreased necrotic cell or LPS induced IL-1β production and LPS induced TNFα production in primary peritoneal macrophages. Furthermore, mefunidone significantly inhibited the phosphorylation of IKKβ/IκB and nuclear transition of NF-κB p65 in peritoneal macrophages stimulated by necrotic cell or lipopolysaccharide. In conclusion, mefunidone serves as a novel anti-inflammatory agent that attenuates UUO-induced renal interstitial inflammation and fibrosis, possibly through suppressing IKKβ phosphorylation.