Universität zu Köln

Abkhezr, Mousa, Kim, Eun Young, Roshanravan, Hila, Nikolos, Fotis, Thomas, Christoforos, Hagmann, Henning, Benzing, Thomas and Dryer, Stuart E. (2015). RETRACTED: Pleiotropic signaling evoked by tumor necrosis factor in podocytes (Retracted article. See vol. 310, pg. F1423, 2016). Am. J. Physiol.-Renal Physiol., 309 (2). S. F98 - 11. BETHESDA: AMER PHYSIOLOGICAL SOC. ISSN 1522-1466

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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-kappa B p65-RelA followed by increased tyrosine phosphorylation of STAT3. STAT3 activation was blocked by the NF-kappa B inhibitor JSH-23 and by the STAT3 inhibitor stattic, whereas TNF-evoked NF-kappa B 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, La3+-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Abkhezr, Mousa UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Eun Young UNSPECIFIED UNSPECIFIED UNSPECIFIED Roshanravan, Hila UNSPECIFIED UNSPECIFIED UNSPECIFIED Nikolos, Fotis UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Christoforos UNSPECIFIED UNSPECIFIED UNSPECIFIED Hagmann, Henning UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Dryer, Stuart E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-398795
DOI:	10.1152/ajprenal.00146.2015
Journal or Publication Title:	Am. J. Physiol.-Renal Physiol.
Volume:	309
Number:	2
Page Range:	S. F98 - 11
Date:	2015
Publisher:	AMER PHYSIOLOGICAL SOC
Place of Publication:	BETHESDA
ISSN:	1522-1466
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; FACTOR-ALPHA; TRPC6 CHANNELS; ANGIOTENSIN-II; TNF-ALPHA; NEPHROTIC SYNDROME; MONONUCLEAR-CELLS; GENE-EXPRESSION; ACTIVATION Multiple languages Physiology; Urology & Nephrology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39879