title: Involvement of NF-κBIZ and related cytokines in age-associated renal fibrosis.
abstract: Chronic inflammation is a major contributor to age-related nephropathic changes, including renal fibrosis. In this study, various experimental paradigms were designed to delineate the role played by NF-κBIZ (also known as IκBζ) in age-associated renal fibrosis. Analyses based on RNA-sequencing findings obtained by next generation sequencing (NGS) revealed the upregulations of NF-κBIZ and of IL-6 and MCP-1 (both known to be regulated by NF-κBIZ) during aging. The up-regulation of NF-κBIZ in aged rat kidneys coincided with increased macrophage infiltration. In LPS-treated macrophages, oxidative stress was found to play a pivotal role in NF-κBIZ expression, suggesting age-related oxidative stress is associated with NF-κBIZ activation. Furthermore, these in vitro findings were confirmed in LPS-treated old rats, which showed higher levels of oxidative stress and NF-κBIZ in kidneys than LPS-treated young rats. Additional in vitro experiments using macrophages and kidney fibroblasts demonstrated NF-κBIZ and related cytokines participate in fibrosis. In particular, increased levels of NF-κBIZ-associated cytokines in macrophages significantly up-regulated TGF-β induced kidney fibroblast activation. Moreover, experiments with NF-κBIZ knocked down macrophages showed reduced TGF-β-induced kidney fibroblast activation. The findings of the present study provide evidence regarding an involvement of NF-κBIZ in age-associated progressive renal fibrosis and provides potential targets for its prevention.
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Hyeong Oh
authors.initials: HO
authors.lastname: Jeong
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Bonggi
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.|. Systems Toxicology Research Center, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
authors.forename: Daeui
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Yeun Ja
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Eun Kyeong
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Kyung Mok
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: June Whoun
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Byung Pal
authors.initials: BP
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D020672:I-kappa B Proteins / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016207:Cytokines; D020672:I-kappa B Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; C000626389:NFKBIZ protein, rat; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; C482199:lipopolysaccharide, E coli O55-B5
keywords: NF-κBIZ; aging; inflammation; renal fibrosis