Expression of silencer of death domains and death-receptor-3 in normal human kidney and in rejecting renal transplants.
We have previously reported the pattern of cellular expression of tumor necrosis factor receptors (TNFR) in human kidney and their altered expression in transplant rejection. We have extended our studies to examine the expression of Silencer of Death Domains (SODD), a protein that binds to the cytoplasmic portion of TNFR1 to inhibit signaling in the absence of ligand. In normal human kidney SODD is expressed in glomerular endothelial cells where it colocalizes with TNFR1. During acute rejection both SODD and TNFR1 are lost from glomeruli, but we found strong expression of SODD on the luminal surface of tubular epithelial cells. This occurs in the absence of detectable TNFR1 expression, suggesting that SODD could interact with other proteins at these sites. Several other members of the TNF superfamily, including Fas and death receptors (DR)-3, -4, and -5, also contain intracellular death domains, but SODD only interacts with the death domain of DR3. We therefore studied the expression of DR3 in human kidney, and report that this death receptor is up-regulated in renal tubular epithelial cells and endothelial cells of some interlobular arteries, in parallel with SODD, during acute transplant rejection. In less severe rejection episodes, DR3 and SODD were more focally induced, generally at sites of mononuclear cell infiltrates. In ischemic allografts, eg, with acute tubular necrosis but no cellular rejection, DR3 was induced on tubular epithelial cells and on glomerular endothelial cells. These data confirm that TNF receptor family members are expressed in a regulated manner during renal transplant rejection, and identify DR3 as a potential inducible mediator of tubular inflammation and injury.
Al-Lamki
Rafia S
RS
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. rsma2@hermes.cam.ac.uk
Wang
Jun
J
Thiru
Sathia
S
Pritchard
Nicholas R
NR
Bradley
J Andrew
JA
Pober
Jordan S
JS
Bradley
John R
JR
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006084:Graft Rejection / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007633:Keratins / Q000378:metabolism; D007668:Kidney / Q000502:physiology* / Q000648:ultrastructure; D016030:Kidney Transplantation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C116906:BAG4 protein, human; D002352:Carrier Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; C506033:TNFRSF25 protein, human; D007633:Keratins