title: Increased susceptibility to acute kidney injury due to endoplasmic reticulum stress in mice lacking tumor necrosis factor-α and its receptor 1.
abstract: Endoplasmic reticulum (ER) stress is actively involved in acute organ injury. Since tumor necrosis factor α (TNFα) plays a role in acute kidney injury, and induces ER stress and cell death in vitro, we examined the contribution of TNFα to acute kidney ER stress induced by tunicamycin. Contrary to expectation, tunicamycin caused much more severe kidney injury in TNFα-/- than in wild-type mice. The major site of kidney injury in TNFα-/- mice was proximal tubules, which showed extensive cell vacuolation, lipid accumulation, and apoptosis. Reconstitution of TNFα-/- mice with TNFα 24 h before tunicamycin injection reversed the susceptibility. When TNFα-receptor-deficient mice were treated with tunicamycin, severe renal injury developed in TNFR1-/- but not TNFR2-/- mice, suggesting this aspect of TNFα action was through TNF receptor-1 (TNFR1). In response to tunicamycin-induced acute ER stress, kidneys from neither TNFα-/- nor TNFR1-/- mice showed a significant increase in phosphorylated eukaryotic translation initiation factor 2α (eIF2α), a key step in ER stress regulation. Moreover, proximal tubular cells from TNFR1-/- mice did not show increased eIF2α phosphorylation in response to tunicamycin and were susceptible to ER stress-induced cell death. Finally, treatment of proximal tubule cells isolated from TNFR1-/- mice with an inhibitor of eIF2α phosphatase increased the levels of phosphorylated eIF2α and substantially reduced tunicamycin-induced cell death. Thus, disruption of TNFR1 signaling leads to dysregulation of eIF2α and increased susceptibility to acute ER stress injury in the kidney.
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine; New York, New York, USA; Fujian Key Laboratory of Transplant Biology, Donfang Hospital, Fuzhou, Fujian, China.
authors.forename: Lianghu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine; New York, New York, USA.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine; New York, New York, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Donfang Hospital, Fuzhou, Fujian, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine; New York, New York, USA.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Grosjean
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Satlin
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
authors.affiliation: Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Sands
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine; New York, New York, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Striker
authors.affiliation: Fujian Key Laboratory of Transplant Biology, Donfang Hospital, Fuzhou, Fujian, China. Electronic address: tanjm156@yahoo.com.cn.
authors.forename: Jianming
authors.initials: J
authors.lastname: Tan
authors.affiliation: Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine; New York, New York, USA; Fujian Key Laboratory of Transplant Biology, Donfang Hospital, Fuzhou, Fujian, China. Electronic address: feng.zheng@mssm.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency* / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics; D012720:Severity of Illness Index; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000235:genetics; D014415:Tunicamycin
chemical_list: D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D014415:Tunicamycin; C019363:eIF-2 phosphatase; D010749:Phosphoprotein Phosphatases