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

被引:65
|
作者
Bruggeman, Leslie A. [1 ,2 ]
Drawz, Paul E. [1 ,2 ]
Kahoud, Nicole [5 ,6 ]
Lin, Ke [3 ,4 ]
Barisoni, Laura [3 ,4 ]
Nelson, Peter J. [5 ,6 ]
机构
[1] Case Western Reserve Univ, Metrohlth Med Ctr, Sch Med, Dept Med, Cleveland, OH 44109 USA
[2] Case Western Reserve Univ, Metrohlth Med Ctr, Sch Med, Rammelkamp Ctr Educ & Res, Cleveland, OH 44109 USA
[3] NYU, Sch Med, Dept Pathol, New York, NY USA
[4] NYU, Sch Med, Div Nephrol, New York, NY USA
[5] Univ Washington, Div Nephrol, Seattle, WA 98195 USA
[6] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA
基金
美国国家卫生研究院;
关键词
collapsing glomerulopathy; gene expression; glomerulonephritis; HIV-1; inflammation; podocytes; proliferation; tumor necrosis factor; NECROSIS-FACTOR RECEPTORS; COLLAPSING GLOMERULOPATHY; EPITHELIAL-CELLS; IN-VIVO; KIDNEY-DISEASE; UP-REGULATION; EXPRESSION; GLOMERULONEPHRITIS; MICE; NEPHROPATHY;
D O I
10.1038/labinvest.2010.199
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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-kappa B and dose-dependently induced podocyte proliferation, marked by the expression of the podocyte G(1) cyclin and NF-kappa B target gene, cyclin D1. Microarray gene and chemokine protein expression profiling showed a marked pro-inflammatory NF-kappa B signature, and activated podocytes secreting CCL2- and CCL5-induced macrophage migration in transwell assays. Neutralization of TNFR2 on podocytes with blocking antibodies abrogated NF-kappa B activation and the induction of cyclin D1 by TNF-alpha, and identified TNFR2 as the primary receptor that induced I kappa B alpha degradation, the initiating event in NF-kappa B activation. These results suggest that TNFR2 expressed on podocytes and its canonical NF-kappa B 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. Laboratory Investigation (2011) 91, 413-425; doi:10.1038/labinvest.2010.199; published online 10 January 2011
引用
收藏
页码:413 / 425
页数:13
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