title: Foxc1 and Foxc2 are necessary to maintain glomerular podocytes.
abstract: Foxc1 and Foxc2 (Foxc1/2) are transcription factors involved in many biological processes. In adult kidneys, expression of Foxc1/2 is confined to the glomerular epithelial cells, i.e., podocytes. To bypass embryonic lethality of Foxc1/2 null mice, mice ubiquitously expressing inducible-Cre (ROSA26-CreERT2) or mice expressing Cre in podocytes (Nephrin-Cre) were mated with floxed-Foxc1 and floxed-Foxc2 mice. The CreERT2was activated in adult mice by administrations of tamoxifen. Eight weeks after tamoxifen treatment, ROSA26-CreERT2; Foxc1+/flox; Foxc2flox/floxmice developed microalbuminuria, while ROSA26-Cre ERT2; Foxc1flox/flox; Foxc2+/floxmice had no microalbuminuria. The kidneys of conditional-Foxc1/2 null mice showed proteinaceous casts, protein reabsorption droplets in tubules and huge vacuoles in podocytes, indicating severe podocyte injury and massive proteinuria. Comparison of gene expression profiles revealed that Foxc1/2 maintain expression of genes necessary for podocyte function such as podocin and Cxcl12. In addition, mice with an innate podocyte-specific deletion of Foxc1/2 by Nephrin-Cre develop similar podocyte injury. These results demonstrate dose-dependence of Foxc1/2 gene in maintaining the podocyte with a more critical role for Foxc2 than Foxc1 and a critical role of Foxc1/2 in regulating expression of genes that maintain podocyte integrity.
authors.affiliation: Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. Electronic address: m-motoji@is.icc.u-tokai.ac.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Motojima
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kume
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
mesh_terms: D000419:Albuminuria / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: D054377:Chemokine CXCL12; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; C082078:mesenchyme fork head 1 protein
keywords: FSGS; Foxc1; Foxc2; Podocyte; Proteinuria