title: Podocyte injury induces nuclear translocation of WTIP via microtubule-dependent transport.
abstract: Podocyte structural and transcriptional phenotype plasticity characterizes glomerular injury. Transcriptional activity of WT1 (Wilm's tumor 1) is required for normal podocyte structure and is repressed by the podocyte adherens junction protein, WTIP (WT1 interacting protein). Here we show that WTIP translocated into podocyte nuclei in lipopolysaccharide (LPS)-treated mice, a model of transient nephrotic syndrome. Cultured podocytes, which stably expressed an epitope-tagged WTIP, were treated with LPS. Imaging and cellular fractionation studies demonstrated that WTIP translocated from podocyte cell contacts into nuclei within 6 h and relocalized to cell contacts within 24 h after LPS treatment. LPS-stimulated WTIP nuclear translocation required JNK activity, which assembled a multiprotein complex of the scaffolding protein JNK-interacting protein 3 and the molecular motor dynein. Intact microtubule networks and dynein activity were necessary for LPS-stimulated WTIP translocation. Podocytes expressing sh-Wtip change morphology and demonstrate altered actin assembly in cell spreading assays. Stress signaling pathways initiate WTIP nuclear translocation, and the concomitant loss of WTIP from cell contacts changes podocyte morphology and dynamic actin assembly, suggesting a mechanism that transmits changes in podocyte morphology to the nucleus.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44109.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Case Western Reserve University Center for the Study of Kidney Disease and Biology, Cleveland, Ohio 44109.
authors.forename: Martha
authors.initials: M
authors.lastname: Konieczkowski
authors.affiliation: Case Western Reserve University Center for the Study of Kidney Disease and Biology, Cleveland, Ohio 44109.
authors.forename: Amitava
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Case Western Reserve University Center for the Study of Kidney Disease and Biology, Cleveland, Ohio 44109.
authors.forename: Sam
authors.initials: S
authors.lastname: Schechtman
authors.affiliation: Case Western Reserve University Center for the Study of Kidney Disease and Biology, Cleveland, Ohio 44109.
authors.forename: Shenaz
authors.initials: S
authors.lastname: Khan
authors.affiliation: Case Western Reserve University Center for the Study of Kidney Disease and Biology, Cleveland, Ohio 44109; Department of Medicine, MetroHealth System Campus, Cleveland, Ohio 44109.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Schelling
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ross
authors.affiliation: Case Western Reserve University Center for the Study of Kidney Disease and Biology, Cleveland, Ohio 44109; Department of Medicine, MetroHealth System Campus, Cleveland, Ohio 44109.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bruggeman
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44109; Case Western Reserve University Center for the Study of Kidney Disease and Biology, Cleveland, Ohio 44109; Department of Medicine, MetroHealth System Campus, Cleveland, Ohio 44109. Electronic address: john.sedor@case.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Sedor
mesh_terms: D000199:Actins / Q000737:chemistry; D021581:Active Transport, Cell Nucleus; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D056970:Co-Repressor Proteins; D003598:Cytoskeletal Proteins; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000199:Actins; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D003598:Cytoskeletal Proteins; D008070:Lipopolysaccharides; C484859:WTIP protein, human; C484858:Wtip protein, mouse