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TNFR1‐ and TNFR2‐mediated signaling pathways in human kidney are cell type‐specific and differentially contribute to renal injury
Author(s) -
AlLamki Rafia S.,
Wang Jun,
Vandenabeele Peter,
Bradley J. Andrew,
Thiru Sathia,
Luo Dianghong,
Min Wang,
Pober Jordan S.,
Bradley John R.
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-3841com
Subject(s) - microbiology and biotechnology , kinase , phosphorylation , signal transduction , bruton's tyrosine kinase , apoptosis , ask1 , biology , tyrosine kinase , chemistry , cancer research , protein kinase a , mitogen activated protein kinase kinase , biochemistry
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 Al‐Lamki, R. S., Wang, J., Vandenabeele, P., Bradley, J. A., Thiru, S., Luo, D., Min, W., Pober, J. S., Bradley, J. R. TNFR1‐ and TNFR2‐mediated signaling pathways in human kidney are cell type‐specific and differentially contribute to renal injury. FASEB J. 19, 1637–1645 (2005)