title: Epigenetic repression of Krüppel-like factor 4 through Dnmt1 contributes to EMT in renal fibrosis.
abstract: Krüppel-like factor 4 (KLF4) is a transcription factor which plays divergent roles in a number of physiological or pathological process. However, the expression and role of KLF4 in renal fibrosis remain undetermined. The aim of the present study was to determine the epigenetic alterations of KLF4 and its potential role and mechanisms of action in epithelial-to-mesenchymal transition (EMT) in renal fibrosis. The hypermethylation of the KLF4 promoter accompanied by a decrease in KLF4 expression were observed in mice subjected to unilateral ureteral obstruction (UUO) and in HK-2 cells stimulated with transforming growth factor (TGF)-β1. However, treatment with 5-aza-2'-deoxycytidine attenuated the TGF-β1-induced downregulation of KLF4 and E-cadherin and the upregulation of α-smooth muscle actin (α-SMA) in the HK-2 cells. DNA methyltransferase 1 (Dnmt1) participated in the TGF-β1-mediated hypermethylation of the KLF4 promoter in the HK-2 cells. In addition, functional analysis demonstrated that the overexpression of KLF4 led to an increase in the expression of E-cadherin and zonula occludens-l (ZO-1), and a decrease in the expression of α-SMA and fibroblast-specific protein 1 (FSP-1), thus reversing the effects of the suppression of KLF4. These data suggest that KLF4 inhibits the progression of EMT in renal epithelial cells. In conclusion, our findings demonstrate that KLF4 is downregulated during EMT in renal fibrosis in vivo and in vitro; thus, KLF4 functions as a suppressor of renal fibrogenesis. The hypermethylation of KLF4 directly mediated by Dnmt1 contributes to the progression of EMT in renal epithelial cells. KLF4 promoter methylation may thus be a promising diagnostic marker or therapeutic target in renal fibrosis.
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Xiangcheng
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Qiongjing
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: The Nephrotic Laboratory of Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Yu
mesh_terms: D000818:Animals; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse