TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α

The development of proliferative podocytopathies has been linked to ligation of TNFR2 expressed on the renal parenchyma; however, the TNFR2 positive cells within the kidney responsible for podocyte injury are unknown. We detected de novo expression of TNFR2 on podocytes prior to hyperplastic injury...

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Main Authors:	Bruggeman, Leslie A., Drawz, Paul E., Kahoud, Nicole, Lin, Ke, Barisoni, Laura, Nelson, Peter J.
Format:	Online
Language:	English
Published:	2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075956/

id	pubmed-3075956
recordtype	oai_dc
spelling	pubmed-30759562011-09-01 TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α Bruggeman, Leslie A. Drawz, Paul E. Kahoud, Nicole Lin, Ke Barisoni, Laura Nelson, Peter J. Article The development of proliferative podocytopathies has been linked to ligation of TNFR2 expressed on the renal parenchyma; however, the TNFR2 positive cells within the kidney responsible for podocyte injury are unknown. We detected de novo expression of TNFR2 on podocytes prior to hyperplastic injury in crescentic glomerulonephritis of mice with nephrotoxic nephritis, and in collapsing glomerulopathy of Tg26HIV/nl mice, kd/kd mice, and humans. We further found that serum levels of soluble TNF-α and TNFR2 correlated significantly with renal injury in Tg26HIV/nl mice. Thus, we asked whether ligand binding of TNFR2 on podocytes ex vivo precipitates the characteristic proliferative and pro-inflammatory diseased podocyte phenotypes. Soluble TNF-α activated NF-κB and dose-dependently induced podocyte proliferation, marked by expression of the podocyte G1 cyclin and NF-κB target gene, cyclin D1. Microarray gene and chemokine protein expression profiling showed a marked pro-inflammatory NF-κB signature, and activated podocytes secreting CCL2 and CCL5 induced macrophage migration in transwell assays. Neutralization of TNFR2 on podocytes with blocking antibodies abrogated NF-κB activation and the induction of cyclin D1 by TNF-α, and identified TNFR2 as the primary receptor that induced IκBα degradation, the initiating event in NF-κB activation. These results suggest that TNFR2 expressed on podocytes and its canonical NF-κB signaling may directly interpose the compound pathogenic responses by podocytes to TNF-α, absent other TNFR2 positive renal cell-types in proliferative podocytopathies. 2011-01-10 2011-03 /pmc/articles/PMC3075956/ /pubmed/21221075 http://dx.doi.org/10.1038/labinvest.2010.199 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Bruggeman, Leslie A. Drawz, Paul E. Kahoud, Nicole Lin, Ke Barisoni, Laura Nelson, Peter J.
spellingShingle	Bruggeman, Leslie A. Drawz, Paul E. Kahoud, Nicole Lin, Ke Barisoni, Laura Nelson, Peter J. TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α
author_facet	Bruggeman, Leslie A. Drawz, Paul E. Kahoud, Nicole Lin, Ke Barisoni, Laura Nelson, Peter J.
author_sort	Bruggeman, Leslie A.
title	TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α
title_short	TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α
title_full	TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α
title_fullStr	TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α
title_full_unstemmed	TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α
title_sort	tnfr2 interposes the proliferative and nf-κb-mediated inflammatory response by podocytes to tnf-α
description	The development of proliferative podocytopathies has been linked to ligation of TNFR2 expressed on the renal parenchyma; however, the TNFR2 positive cells within the kidney responsible for podocyte injury are unknown. We detected de novo expression of TNFR2 on podocytes prior to hyperplastic injury in crescentic glomerulonephritis of mice with nephrotoxic nephritis, and in collapsing glomerulopathy of Tg26HIV/nl mice, kd/kd mice, and humans. We further found that serum levels of soluble TNF-α and TNFR2 correlated significantly with renal injury in Tg26HIV/nl mice. Thus, we asked whether ligand binding of TNFR2 on podocytes ex vivo precipitates the characteristic proliferative and pro-inflammatory diseased podocyte phenotypes. Soluble TNF-α activated NF-κB and dose-dependently induced podocyte proliferation, marked by expression of the podocyte G1 cyclin and NF-κB target gene, cyclin D1. Microarray gene and chemokine protein expression profiling showed a marked pro-inflammatory NF-κB signature, and activated podocytes secreting CCL2 and CCL5 induced macrophage migration in transwell assays. Neutralization of TNFR2 on podocytes with blocking antibodies abrogated NF-κB activation and the induction of cyclin D1 by TNF-α, and identified TNFR2 as the primary receptor that induced IκBα degradation, the initiating event in NF-κB activation. These results suggest that TNFR2 expressed on podocytes and its canonical NF-κB signaling may directly interpose the compound pathogenic responses by podocytes to TNF-α, absent other TNFR2 positive renal cell-types in proliferative podocytopathies.
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075956/
_version_	1611449267881246720

TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α

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