TNFα Signaling Regulates Cystic Epithelial Cell Proliferation through Akt/mTOR and ERK/MAPK/Cdk2 Mediated Id2 Signaling

Tumor necrosis factor alpha (TNF alpha) is present in cyst fluid and promotes cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, the cross-talk between TNF alpha and PKD associated signaling pathways remains elusive. In this study, we found that stimulation of renal epithelial cells with TNF alpha or RANKL (receptor activator of NF-kappa B ligand), a member of the TNF alpha 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 TNF alpha/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. TNF alpha 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 TNF alpha signaling in regulating cystic renal epithelial cell proliferation in ADPKD.