Dissemin is shutting down on January 1st, 2025

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Wiley Open Access, FASEB Journal, 12(19), p. 1637-1645, 2005

DOI: 10.1096/fj.05-3841com

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TNFR1-and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Data provided by SHERPA/RoMEO

Abstract

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.