TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α.
TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α.
复制标题
DOI：
10.1038/labinvest.2010.199
复制
发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
增生性足细胞病变的发生与肾实质上表达的TNFR2的结扎有关；然而，肾脏内负责足细胞损伤的TNFR2阳性细胞尚不清楚。在肾毒性肾炎小鼠的新月体肾炎、Tg26HIV/NL小鼠、kd/kd小鼠和人的塌陷性肾小球病变中，我们检测了增生性损伤前足细胞上TNFR2的从头表达。我们进一步发现血清中可溶性肿瘤坏死因子-α和肿瘤坏死因子受体2水平与Tg26HIV/NL小鼠肾脏损伤显著相关。因此，我们询问了TNFR2的配体与足细胞的体外结合是否会导致特征性的增殖性和促炎性足细胞表型。可溶性肿瘤坏死因子-α可激活NF-κB，并呈剂量依赖性地诱导足细胞增殖，表现为足细胞G1期细胞周期蛋白和核因子-κB靶基因细胞周期蛋白D1的表达。微阵列基因和趋化因子蛋白表达谱显示明显的促炎因子-κB特征，并在Transwell分析中激活了分泌CCL2和CCL5的足细胞诱导巨噬细胞迁移。用阻断抗体中和足细胞上的肿瘤坏死因子受体2可抑制NF-κB的激活和肿瘤坏死因子α对细胞周期蛋白D1的诱导，并确认肿瘤坏死因子受体2是诱导IκBα降解的主要受体，而IκB DNA降解是NF-DNA B活化的起始事件。这些结果提示，在增殖性足细胞病变中，足细胞表达的TNFR2及其典型的NF-κB信号可能直接干预足细胞对肿瘤坏死因子-α的复合致病反应，而在增生性足细胞病变中缺乏其他类型的TNFR-2阳性肾细胞。
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.