Int J Biol Sci 2020; 16(13):2340-2356. doi:10.7150/ijbs.46573

Research Paper

KLF6 Acetylation Promotes Sublytic C5b-9-Induced Production of MCP-1 and RANTES in Experimental Mesangial Proliferative Glomerulonephritis

Tianyi Yu1*, Yajuan Gong1*, Yu Liu1, Lu Xia1, Chenhui Zhao2, Longfei Liu1, Mengxiao Xie1, Zhijiao Wu1, Dan Zhao1, Wen Qiu1, Yingwei Wang1, Jing Zhang1,3✉, Mingde Ji4✉

1. Department of Immunology, Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
2. Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
3. Key Laboratory of Antibody Technology of Ministry of Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
4. Department of Laboratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China.
*These authors contributed equally to this work.

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Citation:
Yu T, Gong Y, Liu Y, Xia L, Zhao C, Liu L, Xie M, Wu Z, Zhao D, Qiu W, Wang Y, Zhang J, Ji M. KLF6 Acetylation Promotes Sublytic C5b-9-Induced Production of MCP-1 and RANTES in Experimental Mesangial Proliferative Glomerulonephritis. Int J Biol Sci 2020; 16(13):2340-2356. doi:10.7150/ijbs.46573. Available from http://www.ijbs.com/v16p2340.htm

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Abstract

Rat Thy-1 nephritis (Thy-1N) is an experimental mesangial proliferative glomerulonephritis (MsPGN) for studying human MsPGN. Although sublytic C5b-9 complex formation on glomerular mesangial cells (GMCs) and renal MCP-1 and RANTES production in rats with Thy-1N have been proved, the role and mechanism of MCP-1 or RANTES synthesis in GMCs induced by sublytic C5b-9 are poorly elucidated. In this study, we first found the expression of transcription factor (KLF6), co-activator (KAT7) and chemokines (MCP-1 and RANTES) was all up-regulated both in renal tissue of Thy-1N rats (in vivo) and in sublytic C5b-9-induced GMCs (in vitro). Further in vitro experiments revealed that KLF6 bound to MCP-1 promoter (-297 to -123 nt) and RANTES promoter (-343 to -191 nt), leading to MCP-1 and RANTES gene transcription. Meanwhile, KAT7 also bound to the same region of MCP-1 and RANTES promoter in a KLF6-dependent manner, and KLF6 was acetylated by KAT7 at lysine residue 100, which finally promoted MCP-1 and RANTES expression. Moreover, our in vivo experiments discovered that knockdown of renal KAT7 or KLF6 gene obviously reduced MCP-1 and RANTES production, GMCs proliferation, ECM accumulation, and proteinuria secretion in Thy-1N rats. Collectively, our study indicates that sublytic C5b-9-induced MCP-1 and RANTES synthesis is associated with KAT7-mediated KLF6 acetylation and elevated KLF6 transcriptional activity, which might provide a new insight into the pathogenesis of rat Thy-1N and human MsPGN.

Keywords: KLF6, acetylation, sublytic C5b-9, MCP-1, RANTES, Thy-1 nephritis