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KLF6 Acetylation Promotes Sublytic C5b-9-Induced Production of MCP-1 and RANTES in Experimental Mesangial Proliferative Glomerulonephritis.
International Journal of Biological Sciences ( IF 8.2 ) Pub Date : 2020-06-20 , DOI: 10.7150/ijbs.46573
Tianyi Yu 1 , Yajuan Gong 1 , Yu Liu 1 , Lu Xia 1 , Chenhui Zhao 2 , Longfei Liu 1 , Mengxiao Xie 1 , Zhijiao Wu 1 , Dan Zhao 1 , Wen Qiu 1 , Yingwei Wang 1 , Jing Zhang 1, 3 , Mingde Ji 4
Affiliation  

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.

中文翻译:

KLF6 乙酰化促进亚裂解 C5b-9 诱导的 MCP-1 和 RANTES 在实验性系膜增生性肾小球肾炎中的产生。

大鼠 Thy-1 肾炎 (Thy-1N) 是一种用于研究人类 MsPGN 的实验性系膜增生性肾小球肾炎 (MsPGN)。虽然已经证明了在 Thy-1N 大鼠肾小球系膜细胞 (GMCs) 和肾 MCP-1 和 RANTES 产生的亚溶 C5b-9 复合物的形成,但 MCP-1 或 RANTES 合成在亚溶 C5b-诱导的 GMC 中的作用和机制9 不详。在这项研究中,我们首先发现转录因子(KLF6)、共激活因子(KAT7)和趋化因子(MCP-1 和 RANTES)在 Thy-1N 大鼠(​​体内)和在亚裂解 C5b-9 诱导的 GMC(体外)中。进一步的体外实验表明,KLF6 与 MCP-1 启动子(-297 至 -123 nt)和 RANTES 启动子(-343 至 -191 nt)结合,导致 MCP-1 和 RANTES 基因转录。同时,KAT7 也以 KLF6 依赖性方式与 MCP-1 和 RANTES 启动子的同一区域结合,KLF6 在赖氨酸残基 100 处被 KAT7 乙酰化,最终促进 MCP-1 和 RANTES 表达。此外,我们的体内实验发现,敲除肾脏 KAT7 或 KLF6 基因后,Thy-1N 大鼠的 MCP-1 和 RANTES 产生、GMC 增殖、ECM 积累和蛋白尿分泌明显减少。总的来说,我们的研究表明亚裂解 C5b-9 诱导的 MCP-1 和 RANTES 合成与 KAT7 介导的 KLF6 乙酰化和升高的 KLF6 转录活性有关,这可能为大鼠 Thy-1N 和人类 MsPGN 的发病机制提供新的见解。我们的体内实验发现,敲除肾脏 KAT7 或 KLF6 基因后,Thy-1N 大鼠的 MCP-1 和 RANTES 产生、GMCs 增殖、ECM 积累和蛋白尿分泌明显减少。总的来说,我们的研究表明亚裂解 C5b-9 诱导的 MCP-1 和 RANTES 合成与 KAT7 介导的 KLF6 乙酰化和升高的 KLF6 转录活性有关,这可能为大鼠 Thy-1N 和人类 MsPGN 的发病机制提供新的见解。我们的体内实验发现,敲除肾脏 KAT7 或 KLF6 基因后,Thy-1N 大鼠的 MCP-1 和 RANTES 产生、GMCs 增殖、ECM 积累和蛋白尿分泌明显减少。总的来说,我们的研究表明亚裂解 C5b-9 诱导的 MCP-1 和 RANTES 合成与 KAT7 介导的 KLF6 乙酰化和升高的 KLF6 转录活性有关,这可能为大鼠 Thy-1N 和人类 MsPGN 的发病机制提供新的见解。
更新日期:2020-06-20
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