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

Leslie A. Bruggeman, Paul E. Drawz, Nicole Kahoud, Ke Lin, Laura Barisoni, Peter J. Nelson

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

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-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 the expression of the podocyte G 1 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 IBα 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, in the absence of other TNFR2-positive renal cell types in proliferative podocytopathies.

Original languageEnglish (US)
Pages (from-to)413-425
Number of pages13
JournalLaboratory Investigation
Volume91
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • collapsing glomerulopathy
  • gene expression
  • glomerulonephritis
  • HIV-1
  • inflammation
  • podocytes
  • proliferation
  • tumor necrosis factor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

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