title: Kruppel-like factor 15 (KLF15) is a key regulator of podocyte differentiation.
abstract: Podocyte injury resulting from a loss of differentiation is the hallmark of many glomerular diseases. We previously showed that retinoic acid (RA) induces podocyte differentiation via stimulation of the cAMP pathway. However, many podocyte maturity markers lack binding sites for RA-response element or cAMP-response element (CREB) in their promoter regions. We hypothesized that transcription factors induced by RA and downstream of CREB mediate podocyte differentiation. We performed microarray gene expression studies in human podocytes treated with and without RA to identify differentially regulated genes. In comparison with known CREB target genes, we identified Krüppel-like factor 15 (KLF15), a kidney-enriched nuclear transcription factor, that has been previously shown to mediate cell differentiation. We confirmed that RA increased KLF15 expression in both murine and human podocytes. Overexpression of KLF15 stimulated expression of differentiation markers in both wild-type and HIV-1-infected podocytes. Also, KLF15 binding to the promoter regions of nephrin and podocin was increased in RA-treated podocytes. Although KLF15(-/-) mice at base line had minimal phenotype, lipopolysaccharide- or adriamycin-treated KLF15(-/-) mice had a significant increase in proteinuria and podocyte foot process effacement with a reduction in the expression of podocyte differentiation markers as compared with the wild-type treated mice. Finally, KLF15 expression was reduced in glomeruli isolated from HIV transgenic mice as well as in kidney biopsies from patients with HIV-associated nephropathy and idiopathic focal segmental glomerulosclerosis. These results indicate a critical role of KLF15 in mediating podocyte differentiation and in protecting podocytes against injury.
authors.affiliation: Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Mallipattu
authors.forename: Ruijie
authors.initials: R
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.forename: Steven
authors.initials: S
authors.lastname: Dikman
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.forename: Moin
authors.initials: M
authors.lastname: Saleem
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.forename: Paul
authors.initials: P
authors.lastname: Klotman
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Chuang
authors.forename: John C
authors.initials: JC
authors.lastname: He
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; C414172:KLF15 protein, human; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D014212:Tretinoin