尼福林
足细胞
KLF4公司
生物
表观遗传学
癌症研究
波多辛
DNA甲基化
细胞生物学
表观基因组
转录因子
糖尿病肾病
狭缝隔膜
肾小球硬化
细胞标志蛋白
组蛋白
突触素
局灶节段性肾小球硬化
分子生物学
基因表达
遗传学
基因
肾
蛋白尿
SOX2
作者
Kaori Hayashi,Hiroyuki Sasamura,Mari M. Nakamura,Tatsuhiko Azegami,Hideyo Oguchi,Yusuke Sakamaki,Hiroshi Itoh
摘要
The transcription factor Kruppel-like factor 4 (KLF4) has the ability, along with other factors, to reprogram somatic cells into induced pluripotent stem (iPS) cells. Here, we determined that KLF4 is expressed in kidney glomerular podocytes and is decreased in both animal models and humans exhibiting a proteinuric. Transient restoration of KLF4 expression in podocytes of diseased glomeruli in vivo, either by gene transfer or transgenic expression, resulted in a sustained increase in nephrin expression and a decrease in albuminuria. In mice harboring podocyte-specific deletion of Klf4, adriamycin-induced proteinuria was substantially exacerbated, although these animals displayed minimal phenotypical changes prior to adriamycin administration. KLF4 overexpression in cultured human podocytes increased expression of nephrin and other epithelial markers and reduced mesenchymal gene expression. DNA methylation profiling and bisulfite genomic sequencing revealed that KLF4 expression reduced methylation at the nephrin promoter and the promoters of other epithelial markers; however, methylation was increased at the promoters of genes encoding mesenchymal markers, suggesting selective epigenetic regulation of podocyte gene expression. Together, these results suggest that KLF4 epigenetically modulates podocyte phenotype and function and that the podocyte epigenome can be targeted for direct intervention and reduction of proteinuria.
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