title: Overexpression of transcription factor FOXC2 in cultured human podocytes upregulates injury markers and increases motility.
abstract: Obesity and diabetes-related kidney diseases associate with renal failure and cardiovascular morbidity, and represent a major health issue worldwide. However, the molecular mechanisms leading to their development remain poorly understood. We observed increased expression of transcription factor FoxC2 in the podocytes of obese Zucker rats that are insulin resistant and albuminuric. We also found that depletion of adiponectin, an adipocyte-derived hormone whose secretion is decreased in obesity, upregulated FOXC2 in differentiated human podocytes in vitro. Overexpression of FOXC2 in cultured human podocytes led to increased nuclear expression of FOXC2 associated with a change of cellular morphology. This was accompanied by upregulation of vimentin, a key mesenchymal marker, and active beta-catenin, associated with podocyte injury. We also observed re-organization of the actin cytoskeleton, disrupted localization of the tight junction protein ZO-1, and increased motility of podocytes overexpressing FOXC2. These data indicate that the expression of FOXC2 in podocytes needs to be tightly regulated, and that its overexpression induces a chain of cellular events leading to podocyte dysfunction. These changes may lead to podocyte detachment and depletion ultimately contributing to albuminuria. We also suggest a novel molecular mechanism linking obesity-induced decrease in adiponectin to podocyte dysfunction via upregulation of FOXC2.
authors.affiliation: Department of Pathology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Neeta
authors.initials: N
authors.lastname: Datta
authors.affiliation: Department of Pathology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Sonja
authors.initials: S
authors.lastname: Lindfors
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miura
authors.affiliation: Academic and Children's Renal Unit, Dorothy Hodgkin Building, Bristol BS1, United Kingdom.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Department of Pathology, University of Helsinki, 00290 Helsinki, Finland. Electronic address: sanna.h.lehtonen@helsinki.fi.
authors.forename: Sanna
authors.initials: S
authors.lastname: Lehtonen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D011924:Rats, Zucker; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: D015415:Biomarkers; D051858:Forkhead Transcription Factors; C082078:mesenchyme fork head 1 protein
keywords: Actin; Adiponectin; Beta-catenin; FOXC2; Migration; Vimentin