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

作者：Chung Ki Wung; Jeong Hyeong Oh; Lee Bonggi; Park Daeui; Kim Dae Hyun; Choi Yeun Ja; Lee Eun Kyeong; Kim Kyung Mok; Park June Whoun; Yu Byung Pal; Chung Hae Young^*

来源：Oncotarget, 2017, 8(5): 7315-7327.

DOI：10.18632/oncotarget.14614

• NF-kappa BIZ
• aging
• inflammation
• renal fibrosis

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-kappa BIZ (also known as I kappa B zeta) in age-associated renal fibrosis. Analyses based on RNA-sequencing findings obtained by next generation sequencing (NGS) revealed the upregulations of NF-kappa BIZ and of IL-6 and MCP-1 (both known to be regulated by NF-kappa BIZ) during aging. The up-regulation of NF-kappa BIZ in aged rat kidneys coincided with increased macrophage infiltration. In LPS-treated macrophages, oxidative stress was found to play a pivotal role in NF-kappa BIZ expression, suggesting age-related oxidative stress is associated with NF-kappa BIZ activation. Furthermore, these in vitro findings were confirmed in LPS-treated old rats, which showed higher levels of oxidative stress and NF-kappa BIZ in kidneys than LPS-treated young rats. Additional in vitro experiments using macrophages and kidney fibroblasts demonstrated NF-kappa BIZ and related cytokines participate in fibrosis. In particular, increased levels of NF-kappa BIZ-associated cytokines in macrophages significantly up-regulated TGF-beta induced kidney fibroblast activation. Moreover, experiments with NF-kappa BIZ knocked down macrophages showed reduced TGF-beta-induced kidney fibroblast activation. The findings of the present study provide evidence regarding an involvement of NF-kappa BIZ in age-associated progressive renal fibrosis and provides potential targets for its prevention.

• 出版日期2017-1-31