title: TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α.
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 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-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 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, in the absence of other TNFR2-positive renal cell types in proliferative podocytopathies.
authors.affiliation: Department of Medicine and Rammelkamp Center for Education and Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44109, USA. leslie.bruggeman@case.edu
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bruggeman
authors.forename: Paul E
authors.initials: PE
authors.lastname: Drawz
authors.forename: Nicole
authors.initials: N
authors.lastname: Kahoud
authors.forename: Ke
authors.initials: K
authors.lastname: Lin
authors.forename: Laura
authors.initials: L
authors.lastname: Barisoni
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009393:Nephritis / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*
chemical_list: D018925:Chemokines; D016213:Cyclins; D020672:I-kappa B Proteins; D008024:Ligands; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha