TNFR1- and TNFR2-mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury.
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
Rafia S
RS
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Wang
Jun
J
Vandenabeele
Peter
P
Bradley
J Andrew
JA
Thiru
Sathia
S
Luo
Dianghong
D
Min
Wang
W
Pober
Jordan S
JS
Bradley
John R
JR
D017209:Apoptosis; D001681:Biological Assay; D001706:Biopsy; D049109:Cell Proliferation; D015536:Down-Regulation; D004789:Enzyme Activation; D006801:Humans; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000293:injuries* / Q000378:metabolism*; D007674:Kidney Diseases / Q000473:pathology*; D007680:Kidney Neoplasms / Q000473:pathology; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000096:biosynthesis; D018613:Microscopy, Confocal; D008954:Models, Biological; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013912:Threonine / Q000737:chemistry; D015854:Up-Regulation
D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013912:Threonine; C492367:BMX protein, human; D011505:Protein-Tyrosine Kinases; D048848:MAP Kinase Kinase Kinase 5