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.

The Universal 3D3 Antibody of Human PODXL Is Pluripotent Cytotoxic, and Identifies a Residual Population After Extended Differentiation of Pluripotent Stem Cells

“…The transcription of PODXL has previously been reported to be positively regulated by WT1 and SP1 [51,52], but negatively by p53 [53]. In agreement with KLF4 and WT1 regulation of PODXL, WT1 and KLF4 are also critical for podocyte functions [54,55]. Immunohistochemistry of H1-teratoma with antibody 3D3, and human OCT4 antibody.…”

Matrix-Stiffness–Regulated Inverse Expression of Krüppel-Like Factor 5 and Krüppel-Like Factor 4 in the Pathogenesis of Renal Fibrosis

“…33,34 Klf4 in glomerular podocytes facilitates cell function and a reduction in proteinuria. 35 Here, we report that inverse expression of Klf5 and Klf4 was switched between soft and stiff matrices. Yes-associated protein 1 (YAP1)-transduced mechanical cues from matrix stiffness may regulate the inverse expression of Klf5 and Klf4, subsequently deciding the cellular fate.…”

Krüppel-like factors in mammalian stem cells and development

“…Interestingly, it was also reported that salutary benefits of glucocorticoids in the kidney are mediated by KLF15 . Furthermore, it was recently reported that transcriptional regulation of KLF6 enhances mitochondrial cytochrome oxidase activity in the setting of podocyte stress , and KLF4 increases the expression of genes involved in maintenance of the renal filtration barrier by reducing methylation in their promoter region (Hayashi et al, 2014). Finally, haploinsufficiency of Klf5 in collecting duct cells exacerbates the inflammatory response in murine models of kidney fibrosis (Fujiu et al, 2011).…”