title: The regulation of the UCH-L1 gene by transcription factor NF-κB in podocytes.
abstract: 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-κB is thought to be the predominant risk factor for kidney disease; therefore, it is postulated that UCH-L1 may be one of the NF-κB target genes. In this study, we investigated the involvement of NF-κB activation in the regulation of UCH-L1 expression and the function of murine podocytes. Stimulation of podocytes with the cytokines TNF-α and IL-1β up-regulated UCH-L1 expression rapidly at the mRNA and protein levels and the NF-κB-specific inhibitor pyrrolidine dithiocarbamate resulted in down-regulation. NF-κB 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-κB and UCH-L1 increased in immunohistochestry staining and were positively correlated. Activation of NF-κB up-regulates UCH-L1 expression following changing of other podocytes molecules, such as nephrin and snail. These results suggest that activation of the NF-κB 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-κB on specific target molecules of podocytes, and suggest that targeting the NF-κB-UCH-L1 interaction could be a novel therapeutic strategy for the treatment of podocyte lesions and proteinuria.
authors.affiliation: Department of Pathology and Key Laboratory of Molecular Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China. 10111010056@fudan.edu.cn
authors.forename: Hongxia
authors.initials: H
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Ruimin
authors.initials: R
authors.lastname: Hu
authors.forename: Weili
authors.initials: W
authors.lastname: Luo
authors.forename: Xing
authors.initials: X
authors.lastname: Mao
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Zhao
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D016384:Consensus Sequence; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology; D007678:Kidney Glomerulus / Q000378:metabolism; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008181:Lupus Nephritis / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D050199:Podocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D051996:Transcription Factor RelA / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D049410:Luciferases, Renilla; D008565:Membrane Proteins; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D043222:Ubiquitin Thiolesterase; C498144:Rela protein, mouse; C113267:nephrin; C496976:Uchl1 protein, mouse