title: DR3 signaling protects against cisplatin nephrotoxicity mediated by tumor necrosis factor.
abstract: The expression of death receptor 3 (DR3), a member of the tumor necrosis factor (TNF) receptor superfamily, is up-regulated in human tubular epithelial cells (TECs) during renal injury, but its function in this setting remains unknown. We used cisplatin to induce renal injury in wild-type (DR3(+/+)) or congenitally deficient DR3(-/-) mice to examine the in vivo role of DR3. Cisplatin induced the expression of DR3, its ligand, TNF-like ligand 1A (TL1A), and TNF in TECs, as observed in human renal injury. Cisplatin increased apoptotic death of DR3(-/-) TECs by twofold compared with DR3(+/+) TECs, whereas it reduced the number of tubules expressing phospho-NF-κBp65(Ser276) by 50% at 72 hours. Similar degrees of induction of DR3, TL1A, and TNF, and changes in apoptosis and phospho-NF-κBp65(Ser276), were obtained in mouse kidney organ cultures treated with cisplatin for 3 hours, suggesting a direct effect on TECs. TNF was implicated in mediating cisplatin-induced tubular damage given that the in vivo co-administration of GM6001, an inhibitor of TNF maturation and release, significantly reduced TNF production and tubular damage. Moreover, TNF exacerbated, whereas TL1A reduced, cisplatin-induced apoptosis in the DR3(+/+) mouse proximal tubule cell line, TKPTS. Our data demonstrate that cisplatin-induced nephrotoxicity is mitigated by DR3 signaling, suggesting that this occurs by antagonizing pro-apoptotic signals induced by TNF. Therefore, activating DR3 may be beneficial in reducing acute kidney injury.
authors.affiliation: Department of Medicine, Biomedical Research Center, Addenbrooke's Hospital, Cambridge, United Kingdom. rsma2@hermes.cam.ac.uk
authors.forename: Rafia S
authors.initials: RS
authors.lastname: Al-Lamki
authors.forename: WanHua
authors.initials: W
authors.lastname: Lu
authors.forename: Sarah
authors.initials: S
authors.lastname: Finlay
authors.forename: Jason P
authors.initials: JP
authors.lastname: Twohig
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
authors.forename: Aviva M
authors.initials: AM
authors.lastname: Tolkovsky
authors.forename: John R
authors.initials: JR
authors.lastname: Bradley
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004151:Dipeptides; D008024:Ligands; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D016328:NF-kappa B; D011480:Protease Inhibitors; D053219:Receptors, Tumor Necrosis Factor, Member 25; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; D002945:Cisplatin