TNFα signaling regulates cystic epithelial cell proliferation through Akt/mTOR and ERK/MAPK/Cdk2 mediated Id2 signaling

PLoS One. 2015 Jun 25;10(6):e0131043. doi: 10.1371/journal.pone.0131043. eCollection 2015.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology*
  • Cyclin-Dependent Kinase 2 / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Inhibitor of Differentiation Protein 2 / metabolism*
  • Kidney / metabolism
  • Kidney / pathology
  • Mice
  • Polycystic Kidney, Autosomal Dominant / metabolism
  • Polycystic Kidney, Autosomal Dominant / pathology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RANK Ligand / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 2
  • RANK Ligand
  • Tumor Necrosis Factor-alpha
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Cyclin-Dependent Kinase 2
  • Extracellular Signal-Regulated MAP Kinases