title: KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria.
abstract: 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.
authors.forename: Kaori
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasamura
authors.forename: Mari
authors.initials: M
authors.lastname: Nakamura
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Azegami
authors.forename: Hideyo
authors.initials: H
authors.lastname: Oguchi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sakamaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D019175:DNA Methylation; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011507:Proteinuria / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014746:Vimentin / Q000235:genetics
chemical_list: D000418:Albumins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D014746:Vimentin; C113267:nephrin; D004317:Doxorubicin