title: Tumor Necrosis Factor-α Increases Claudin-1, 4, and 7 Expression in Tubular Cells: Role in Permeability Changes.
abstract: Tumor necrosis factor-α (TNFα), is a pathogenic cytokine in kidney disease that alters expression of claudins in tubular cells. Previously we showed that in LLC-PK1cells TNFα caused a biphasic change in transepithelial resistance (TER) consisting of an early drop and recovery, followed by a late increase. However, the underlying mechanisms and the role of specific claudins in the TER effect remained incompletely understood. Here we sought to define how TNFα affects claudins 1, 4, and 7 in tubular cells and to correlate their changes with the TER effect. We show that TNFα elevates total and surface levels of Cldn-1, 4, and 7, and increases their mRNA expression through the ERK and JNK pathways. Further, JNK is also important for TNFα-induced changes in claudin-2 expression. Continuous monitoring of TER using Electric cell-substrate impedance sensing (ECIS) reveals that the two phases of the TNFα effect are differently regulated. Specifically, inhibition of the ERK or JNK pathways prevent the late TER increase, but not the early TER effect. Silencing experiments also show that Cldn-1 is necessary for the early TNFα-induced TER change, while all three claudins appear to contribute to the late TER increase. In summary, we define a central role for ERK and JNK in TNFα-induced altered claudin expression and barrier tightening. Together, our current and previous works show that the TNFα-induced early TER effect requires claudin-1, while claudin-2 decrease is a significant mediator of the late TER increase, and elevation in claudin-1, 4, and 7 contribute to a smaller extent. J. Cell. Physiol. 232: 2210-2220, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Ontario, Canada.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Amoozadeh
authors.affiliation: Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Ontario, Canada.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Dan
authors.affiliation: Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Ontario, Canada.
authors.forename: Shaista
authors.initials: S
authors.lastname: Anwer
authors.affiliation: Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Ontario, Canada.
authors.forename: Hsiao Han
authors.initials: HH
authors.lastname: Huang
authors.affiliation: Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Ontario, Canada.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Barbieri
authors.affiliation: Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Ontario, Canada.
authors.forename: Faiza
authors.initials: F
authors.lastname: Waheed
authors.affiliation: Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Ontario, Canada.|Department of Physiology, University of Toronto, Ontario, Canada.
authors.forename: Mazharul
authors.initials: M
authors.lastname: Maishan
authors.affiliation: Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Ontario, Canada.|Department of Surgery, University of Toronto, Ontario, Canada.
authors.forename: Katalin
authors.identifier: http://orcid.org/0000-0002-2490-8422
authors.initials: K
authors.lastname: Szászi
mesh_terms: D000818:Animals; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism*; D062446:Claudin-2 / Q000235:genetics / Q000378:metabolism; D062506:Claudin-4 / Q000235:genetics / Q000378:metabolism*; D017097:Electric Impedance; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007365:Intercellular Junctions / Q000187:drug effects* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D018374:LLC-PK1 Cells; D010539:Permeability / Q000187:drug effects*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D062445:Claudin-1; D062446:Claudin-2; D062506:Claudin-4; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases