The regulation of the UCH-L1 gene by transcription factor NF-¦ÊB in podocytes

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• 作者：Hongxia Zhang¹ ; ^{10111010056@fudan.edu.cn} ; Yu Sun ^{120763119@QQ.com} ; Ruimin Hu ^{huruimin1026@126.com} ; Weili Luo ^{10211010049@fudan.edu.cn} ; Xing Mao ^{maxinemaoxing@126.com} ; Zhonghua Zhao ^{199752@sina.com} ; Qi Chen ^{smubingli@163.com} ; Zhigang Zhang ; ^{zzg@shmu.edu.cn}
• 关键词：Podocyte ; UCH-L1 ; NF-¦ÊB ; Transcription regulation ; Inflammatory kidney disease
• 刊名：Cellular Signalling
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：25
• 期：7
• 页码：1574-1585
• 全文大小：1771 K

文摘

In kidney, the ubiquitin carboxy-terminal hydrolase 1 (UCH-L1) is involved in podocyte injury and proteinuria but details of the mechanism underlying its regulation are not known. Activation of NF-¦ÊB is thought to be the predominant risk factor for kidney disease; therefore, it is postulated that UCH-L1 may be one of the NF-¦ÊB target genes. In this study, we investigated the involvement of NF-¦ÊB activation in the regulation of UCH-L1 expression and the function of murine podocytes. Stimulation of podocytes with the cytokines TNF-¦Á and IL-1¦Â up-regulated UCH-L1 expression rapidly at the mRNA and protein levels and the NF-¦ÊB-specific inhibitor pyrrolidine dithiocarbamate resulted in down-regulation. NF-¦ÊB up-regulates UCH-L1 via binding the ? 300 bp and ? 109 bp sites of its promoter, which was confirmed by the electrophoretic mobility shift assay of DNA-nuclear protein binding. In the renal biopsy from lupus nephritis patients, the expressions of NF-¦ÊB and UCH-L1 increased in immunohistochestry staining and were positively correlated. Activation of NF-¦ÊB up-regulates UCH-L1 expression following changing of other podocytes molecules, such as nephrin and snail. These results suggest that activation of the NF-¦ÊB signaling pathway could be the major pathogenesis to up-regulate UCH-L1 in podocyte injury, followed by the turnover of other molecules, which might result in morphological changes and dysfunction of podocytes. This work help us to understand the effect of NF-¦ÊB on specific target molecules of podocytes, and suggest that targeting the NF-¦ÊB-UCH-L1 interaction could be a novel therapeutic strategy for the treatment of podocyte lesions and proteinuria.