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TNFR2 interposes the proliferative and NF-kappaB-mediated inflammatory response by podocytes to TNF-alpha.

Authors: Bruggeman, LA  Drawz, PE  Kahoud, N  Lin, K  Barisoni, L  Nelson, PJ 
Citation: Bruggeman LA, etal., Lab Invest. 2011 Mar;91(3):413-25. doi: 10.1038/labinvest.2010.199. Epub 2011 Jan 10.
Pubmed: (View Article at PubMed) PMID:21221075
DOI: Full-text: DOI:10.1038/labinvest.2010.199

The development of proliferative podocytopathies has been linked to ligation of tumor necrosis factor receptor 2 (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 before hyperplastic injury in crescentic glomerulonephritis of mice with nephrotoxic nephritis, and in collapsing glomerulopathy of Tg26(HIV/nl) mice, kd/kd mice, and human beings. We further found that serum levels of soluble TNF-alpha and TNFR2 correlated significantly with renal injury in Tg26(HIV/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-alpha activated NF-kappaB and dose-dependently induced podocyte proliferation, marked by the expression of the podocyte G(1) cyclin and NF-kappaB target gene, cyclin D1. Microarray gene and chemokine protein expression profiling showed a marked pro-inflammatory NF-kappaB signature, and activated podocytes secreting CCL2- and CCL5-induced macrophage migration in transwell assays. Neutralization of TNFR2 on podocytes with blocking antibodies abrogated NF-kappaB activation and the induction of cyclin D1 by TNF-alpha, and identified TNFR2 as the primary receptor that induced IkappaBalpha degradation, the initiating event in NF-kappaB activation. These results suggest that TNFR2 expressed on podocytes and its canonical NF-kappaB signaling may directly interpose the compound pathogenic responses by podocytes to TNF-alpha, in the absence of other TNFR2-positive renal cell types in proliferative podocytopathies.

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RGD Object Information
RGD ID: 7245511
Created: 2013-06-07
Species: All species
Last Modified: 2013-06-07
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.