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Tytuł:
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Tumor necrosis factor-α induces claudin-3 upregulation in kidney tubular epithelial cells through NF-κB and CREB1.
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Autorzy:
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Anwer S; Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada.
Branchard E; Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada.
Dan Q; Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada.
Dan A; Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada.
Szászi K; Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada.; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
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Źródło:
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American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2021 Apr 01; Vol. 320 (4), pp. C495-C508. Date of Electronic Publication: 2021 Jan 13.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: Bethesda, Md. : American Physiological Society,
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MeSH Terms:
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Claudin-3/*metabolism
Cyclic AMP Response Element-Binding Protein/*metabolism
Epithelial Cells/*drug effects
Kidney Tubules/*drug effects
NF-kappa B/*metabolism
Tumor Necrosis Factor-alpha/*pharmacology
Animals ; Caco-2 Cells ; Cell Movement/drug effects ; Claudin-3/genetics ; Cyclic AMP Response Element-Binding Protein/genetics ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Epithelial-Mesenchymal Transition/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Kidney Tubules/metabolism ; Kidney Tubules/pathology ; LLC-PK1 Cells ; Male ; Mice ; Signal Transduction ; Swine ; Up-Regulation
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Grant Information:
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PJT-149058 Gouvernement du Canada | Canadian Institutes of Health Research (CIHR); MOP-142409 Gouvernement du Canada | Canadian Institutes of Health Research (CIHR)
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Contributed Indexing:
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Keywords: claudins; epithelial cells; signaling pathways; tight junctions
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Substance Nomenclature:
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0 (Claudin-3)
0 (Cldn3 protein, mouse)
0 (Creb1 protein, mouse)
0 (Cyclic AMP Response Element-Binding Protein)
0 (NF-kappa B)
0 (Tumor Necrosis Factor-alpha)
EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
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Entry Date(s):
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Date Created: 20210113 Date Completed: 20210510 Latest Revision: 20210510
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Update Code:
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20240105
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DOI:
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10.1152/ajpcell.00185.2020
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PMID:
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33439776
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Claudins are essential for tight junction formation and paracellular transport, and they affect key cellular events including proliferation and migration. The properties of tight junctions are dynamically modulated by a variety of inputs. We previously showed that the inflammatory cytokine tumor necrosis factor-α (TNFα), a major pathogenic factor in kidney disease, alters epithelial permeability by affecting the expression of claudin-1, -2, and -4 in kidney tubular cells. Here, we explored the effect of TNFα on claudin-3 (Cldn-3), a ubiquitous barrier-forming protein. We found that TNFα elevated Cldn-3 protein expression in tubular epithelial cells (LLC-PK1 and IMCD3) as early as 3 h post treatment. Bafilomycin A and bortezomib, inhibitors of lysosomal and proteasomes, respectively, reduced Cldn-3 degradation. However, TNFα caused a strong upregulation of Cldn-3 in the presence of bafilomycin, suggesting an effect independent from lysosomes. Blocking protein synthesis using cycloheximide prevented Cldn-3 upregulation by TNFα, verifying the contribution of de novo Cldn-3 synthesis. Indeed, TNFα elevated Cldn-3 mRNA levels at early time points. Using pharmacological inhibitors and siRNA-mediated silencing, we determined that the effect of TNFα on Cldn-3 was mediated by extracellular signal regulated kinase (ERK)-dependent activation of NF-κB and PKA-induced activation of CREB1. These two pathways were turned on by TNFα in parallel and both were required for the upregulation of Cldn-3. Because Cldn-3 was suggested to modulate cell migration and epithelial-mesenchymal transition (EMT), and TNFα was shown to affect these processes, Cldn-3 upregulation may modulate regeneration of the tubules following injury.