Abstract
BackgroundDeath receptors (DRs) play an important role in renal pathology. We have shown that DR3 is inducibly expressed on renal tubular epithelial cells in the setting of inflammatory injuries. In this study we investigate the expression of DR3 in renal endothelial cells and their response to TL1A, the only known ligand of DR3.MethodsWe did RT-PCR, flow cytometry and subcellular immunoblotting to examine the expression and function of DR3 in cells in vitro. We did organ culture of human and mouse tissue to examine expression and signal of DR3 in vivo.ResultsDR3 is expressed in some interstitial vascular endothelial cells (EC) in human kidney in situ; these EC also respond to its ligand TL1A by activating NF-κB. Very low levels of DR3 can be detected on the cell surface of cultured human umbilical vein (HUV) EC, which do not respond to TL1A. HUVEC transfected to overexpress DR3 become responsive to TL1A, assessed by IκBα degradation and E-selectin induction, indicating that the signaling components needed for DR3 responsiveness are expressed. TL1A induces NF-κB activation in EC in renal and cardiac tissue from wild type but not DR3 knock-out mice.ConclusionTL1A and DR3 activate NF-κB in vascular endothelial cells, and can be an important regulator of renal interstitial vascular injury.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2369-15-178) contains supplementary material, which is available to authorized users.
Highlights
Death receptors (DRs) play an important role in renal pathology
We have previously reported that DR3 messenger RNA (mRNA) and protein are induced on non-lymphoid cells of human kidney allografts undergoing acute cellular rejection [9]
Activation of NF-κB by TNF-like molecule 1A (TL1A) in kidney organ culture We have previously reported that endothelial cells (EC) in the interstitium of normal human kidney are positive for DR3 but glomerular EC are negative for DR3 [9]
Summary
Death receptors (DRs) play an important role in renal pathology. We have shown that DR3 is inducibly expressed on renal tubular epithelial cells in the setting of inflammatory injuries. Upon ligand binding, only DR3 and TNFR1 recruit the adaptor TNFR-associated death domain (TRADD) protein and assemble a TRADD-dependent signalling complex that rapidly triggers NF-κB and c-Jun N-terminal kinase (JNK) activation; after a delay of several hours the TRADD signalosome recruits Fas-associated DD (FADD) protein that may trigger apoptosis [5]. Much less is known about regulation and expression of DR3 protein or about its isoforms in non-lymphoid cells. We have previously reported that DR3 mRNA and protein are induced on non-lymphoid cells of human kidney allografts undergoing acute cellular rejection [9]. We observed that DR3 is predominatly up-regulated in tubular epithelial cells but we observed expression of DR3 in some peritubular endothelial cells (EC), albeit not in glomerular EC
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