TNFR1-and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury
TNFR1-and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury
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DOI：
10.1096/fj.05-3841com
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发表时间：
2005-10-01
期刊：
影响因子：
4.8
通讯作者：
Bradley, JR
中科院分区：
文献类型：
--
作者：
Al-Lamki, RS;Wang, J;Bradley, JR
在正常肾脏中，TNFR1 在肾小球和肾小管周围毛细血管 EC 以及一些肾小管细胞中表达，并与丝氨酸 967 处磷酸化的失活凋亡信号调节激酶 1 (ASK1) 共定位。排斥或缺血同种异体肾移植物的活检显示肾小管细胞损伤和增殖，显示 TNFR1 下调和 ASK1 激活 以及肾小管细胞上 TNFR2 的上调，它与磷酸化内皮/上皮酪氨酸激酶 (Etk) 共定位。我们利用受体选择性突变蛋白并评估受体特异性激酶的磷酸化来研究原位 TNF 反应。在器官培养中，TNFR1 特异性突变蛋白将 ASK1 磷酸化为苏氨酸 845，表明激酶激活。 TNFR2 特异性突变蛋白下调肾小球 EC 中的 TNFR1，上调肾小管细胞中的 TNFR2 和 Etk，并诱导 Etk 磷酸化。野生型 TNF 诱导 TNFR2 和 Etk，并激活 ASK1 和 Etk，但不会下调 TNFR1。野生型 TNF 和 TNFR1 特异性突变蛋白触发肾小管细胞凋亡，而野生型 TNF 和 TNFR2 特异性突变蛋白诱导肾小管细胞表达增殖细胞核抗原。患者来源的材料中受调节的 TNFR 对 ASK1 和 Etk 的差异激活提供了对不同位点对 TNF 的多样化和相反反应的解释，以及 TNFR 信号传导的原位生物测定。
In normal kidney, TNFR1 is expressed in glomerular and peritubular capillary EC, and some tubular cells, and colocalizes with inactive apoptosis signal-regulating kinase-1 (ASK1) phosphorylated at serine 967. Biopsies of rejecting or ischemic renal allografts, which show both tubular cell injury and proliferation, display down-regulation of TNFR1 and activation of ASK1 as well as up-regulation of TNFR2 on tubular cells, where it colocalizes with phosphorylated endothelial/epithelial tyrosine kinase (Etk). We have exploited receptor-selective muteins and evaluated phosphorylation of receptor-specific kinases to study TNF responses in situ. In organ culture, a TNFR1-specific mutein changes phosphorylation of ASK1 to threonine 845, indicative of kinase activation. A TNFR2-specific mutein down-regulates TNFR1 in glomerular EC, up-regulates TNFR2 and Etk in tubular cells, and induces phosphorylation of Etk. Wild-type TNF induces TNFR2 and Etk and activates both ASK1 and Etk but does not down-regulate TNFR1. Wild-type TNF and TNFR1-specific mutein trigger tubular cell apoptosis whereas wild-type TNF and TNFR2-specific mutein induce tubular cells to express proliferating cell nuclear antigen. Differential activation of ASK1 and Etk by regulated TNFRs in patient-derived materials provides an explanation for diverse and opposing responses to TNF at distinct sites, and an in situ bioassay of TNFR signaling.