title: Pleiotropic signaling evoked by tumor necrosis factor in podocytes.
abstract: TNF has been implicated in glomerular diseases, but its actions on podocytes are not well understood. Endogenous TNF expression is markedly increased in mouse podocytes exposed to sera from patients with recurrent focal segmental glomerulosclerosis, and TNF is able to increase its own expression in these cells. Exposure of podocytes to TNF increased phosphorylation of NF-κB p65-RelA followed by increased tyrosine phosphorylation of STAT3. STAT3 activation was blocked by the NF-κB inhibitor JSH-23 and by the STAT3 inhibitor stattic, whereas TNF-evoked NF-κB activation was not affected by stattic. TNF treatment increased nuclear accumulation of nuclear factor of activated T cells (NFAT)c1 in podocytes, a process that occurred downstream of STAT3 activation. TNF also increased expression of cyclin D1 but had no effect on cyclin-dependent kinase 4, p27(kip), or podocin. Despite its effects on cyclin D1, TNF treatment for up to 72 h did not cause podocytes to reenter the cell cycle. TNF increased total expression of transient receptor potential (TRP)C6 channels through a pathway dependent on NFATc1 and increased the steady-state expression of TRPC6 subunits on the podocyte cell surface. TNF effects on TRPC6 trafficking required ROS. Consistent with this, La(3+)-sensitive cationic currents activated by a diacylglycerol analog were increased in TNF-treated cells. The effects of TNF on NFATc1 and TRPC6 expression were blocked by cyclosporine A but were not blocked by the pan-TRP inhibitor SKF-96365. TNF therefore influences multiple pathways previously implicated in podocyte pathophysiology and is likely to sensitize these cells to other insults.
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas;
authors.forename: Mousa
authors.initials: M
authors.lastname: Abkhezr
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas;
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas;
authors.forename: Hila
authors.initials: H
authors.lastname: Roshanravan
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas; and.
authors.forename: Fotis
authors.initials: F
authors.lastname: Nikolos
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas; Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas; and.
authors.forename: Christoforos
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Department of Internal Medicine, University of Cologne, Cologne, Germany;
authors.forename: Henning
authors.initials: H
authors.lastname: Hagmann
authors.affiliation: Department of Internal Medicine, University of Cologne, Cologne, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas; Division of Nephrology, Baylor College of Medicine, Houston, Texas sdryer@uh.edu.
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Dryer
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D014409:Tumor Necrosis Factor-alpha
keywords: glomerulosclerosis; inflammation; podocyte; transient receptor potential cation channel, subfamily C, member 6; tumor necrosis factor