title: Mefunidone ameliorates renal inflammation and tubulointerstitial fibrosis via suppression of IKKβ phosphorylation.
abstract: 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 14days 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.
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Xiangning
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Pathology, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Qiongjing
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Xie
authors.affiliation: Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Sisi
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Zhangzhe
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Physiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan 410013, China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Respiration, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Nephrology, Changsha central hospital, Changsha, Hunan 410000, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Medical Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
authors.forename: Gaoyun
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan 410008, China. Electronic address: taolj@csu.edu.cn.
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy; D053583:Interleukin-1beta / Q000235:genetics; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014517:Ureteral Obstruction / Q000473:pathology
chemical_list: C000607330:1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010879:Piperazines; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase
keywords: IKKβ/IκB; Inflammatory response; Macrophages; NALP3; Renal tubulointerstitial fibrosis