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

Zhou JX, Fan LX, Li X, Calvet JP, Li X - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Inhibition of mTOR with rapamycin blocks the upregulation of Id2 induced by TNFα and RANKL.Pkd1 wild-type and Pkd1  MEK cells were not treated (C) or treated with TNFα (T) (20 ng/ml) (A), RANKL (100 ng/ml) (B) in the absence or presence (Rap) of rapamycin (10 nM) for 3 hours. The expression of Id2 and phospho-S6 (p-S6) were analyzed by western blot. The numbers at the bottom indicate the relative intensities of the Id2 bands, which are normalized to actin.
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pone.0131043.g004: Inhibition of mTOR with rapamycin blocks the upregulation of Id2 induced by TNFα and RANKL.Pkd1 wild-type and Pkd1 MEK cells were not treated (C) or treated with TNFα (T) (20 ng/ml) (A), RANKL (100 ng/ml) (B) in the absence or presence (Rap) of rapamycin (10 nM) for 3 hours. The expression of Id2 and phospho-S6 (p-S6) were analyzed by western blot. The numbers at the bottom indicate the relative intensities of the Id2 bands, which are normalized to actin.

Mentions: Next, we examined the relationship between mTOR activation and Id2 expression upon TNFα and RANKL treatment in Pkd1 wild type and mutant MEK cells. For this purpose, Pkd1 wild type and mutant MEK cells were induced with TNFα or RANKL in the absence and presence of rapamycin, and Id2 protein levels were analyzed by western blot. We found that rapamycin completely blocked the induction of Id2 protein in these cells upon TNFα and RANKL treatment (Fig 4). These results suggested that activation of mTOR contributes to Id2 upregulation induced by TNFα and RANKL in renal epithelial cells.


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

Zhou JX, Fan LX, Li X, Calvet JP, Li X - PLoS ONE (2015)

Inhibition of mTOR with rapamycin blocks the upregulation of Id2 induced by TNFα and RANKL.Pkd1 wild-type and Pkd1  MEK cells were not treated (C) or treated with TNFα (T) (20 ng/ml) (A), RANKL (100 ng/ml) (B) in the absence or presence (Rap) of rapamycin (10 nM) for 3 hours. The expression of Id2 and phospho-S6 (p-S6) were analyzed by western blot. The numbers at the bottom indicate the relative intensities of the Id2 bands, which are normalized to actin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482222&req=5

pone.0131043.g004: Inhibition of mTOR with rapamycin blocks the upregulation of Id2 induced by TNFα and RANKL.Pkd1 wild-type and Pkd1 MEK cells were not treated (C) or treated with TNFα (T) (20 ng/ml) (A), RANKL (100 ng/ml) (B) in the absence or presence (Rap) of rapamycin (10 nM) for 3 hours. The expression of Id2 and phospho-S6 (p-S6) were analyzed by western blot. The numbers at the bottom indicate the relative intensities of the Id2 bands, which are normalized to actin.
Mentions: Next, we examined the relationship between mTOR activation and Id2 expression upon TNFα and RANKL treatment in Pkd1 wild type and mutant MEK cells. For this purpose, Pkd1 wild type and mutant MEK cells were induced with TNFα or RANKL in the absence and presence of rapamycin, and Id2 protein levels were analyzed by western blot. We found that rapamycin completely blocked the induction of Id2 protein in these cells upon TNFα and RANKL treatment (Fig 4). These results suggested that activation of mTOR contributes to Id2 upregulation induced by TNFα and RANKL in renal epithelial cells.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus