Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Involvement of NF-κBIZ and related cytokines in age-associated renal fibrosis

Ki Wung Chung, Hyeong Oh Jeong, Bonggi Lee, Daeui Park, Dae Hyun Kim, Yeun Ja Choi, Eun Kyeong Lee, Kyung Mok Kim, June Whoun Park, Byung Pal Yu and Hae Young Chung _

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Oncotarget. 2017; 8:7315-7327. https://doi.org/10.18632/oncotarget.14614

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Abstract

Ki Wung Chung1, Hyeong Oh Jeong1, Bonggi Lee1, Daeui Park1,2, Dae Hyun Kim1, Yeun Ja Choi1, Eun Kyeong Lee1, Kyung Mok Kim1, June Whoun Park1, Byung Pal Yu3 and Hae Young Chung1

1 Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea

2. Systems Toxicology Research Center, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea

3 Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

Correspondence to:

Hae Young Chung, email:

Keywords: NF-κBIZ, aging, inflammation, renal fibrosis

Received: July 13, 2016 Accepted: January 04, 2017 Published: January 12, 2017

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.


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