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

Rafia S. Al-Lamki^*, Jun Wang^*, Peter Vandenabeele, J. Andrew Bradley, Sathia Thiru, Dianghong Luo^||, Wang Min^||, Jordan S. Pober^|| and John R. Bradley^*,1

Departments of
^* Medicine,
Pathology, and
Surgery, University of Cambridge, Addenbrooke’s Hospital, Cambridge; Department of Molecular Biomedical Research, Flanders’ Interuniversity Institute for Biotechnology (VIB),
Interdepartmental Program in Vascular Biology and Transplantation, Gent University, Gent, Belgium; and
^|| Department of Pathology, Boyer Centre for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

¹ Correspondence: Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: john.bradley{at}addenbrookes.nhs.uk

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.

Key Words: TNF • ASK1 • Etk • apoptosis • proliferation

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