title: TNFα signaling regulates cystic epithelial cell proliferation through Akt/mTOR and ERK/MAPK/Cdk2 mediated Id2 signaling.
abstract: Tumor necrosis factor alpha (TNFα) is present in cyst fluid and promotes cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, the cross-talk between TNFα and PKD associated signaling pathways remains elusive. In this study, we found that stimulation of renal epithelial cells with TNFα or RANKL (receptor activator of NF-κB ligand), a member of the TNFα cytokine family, activated either the PI3K pathway, leading to AKT and mTOR mediated the increase of Id2 protein, or MAPK and Cdk2 to induce Id2 nuclear translocation. The effects of TNFα/RANKL on increasing Id2 protein and its nuclear translocation caused significantly decreased mRNA and protein levels of the Cdk inhibitor p21, allowing increased cell proliferation. TNFα levels increase in cystic kidneys in response to macrophage infiltration and thus might contribute to cyst growth and enlargement during the progression of disease. As such, this study elucidates a novel mechanism for TNFα signaling in regulating cystic renal epithelial cell proliferation in ADPKD.
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, United States of America.
authors.forename: Julie X
authors.initials: JX
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, United States of America.
authors.forename: Lucy X
authors.initials: LX
authors.lastname: Fan
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, United States of America.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America.
authors.forename: James P
authors.initials: JP
authors.lastname: Calvet
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; Kidney Institute, University of Kansas Medical Center, Kansas City, KS 66160, United States of America; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, United States of America.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053245:RANK Ligand / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases