title: The A20 gene protects kidneys from ischaemia/reperfusion injury by suppressing pro-inflammatory activation.
abstract: Ischaemia followed by reperfusion (I/R) can induce inflammation and injury and is a risk factor for delayed graft function and rejection of transplanted kidneys. Inflammation is regulated by NF-kappaB transcription factors which induce pro-inflammatory molecules in endothelial cells (EC). We examined whether A20, a negative regulator of NF-kappaB, can protect kidneys from I/R injury. To mimic the fluctuations in endothelial oxygenation that occur during I/R we exposed cultured human umbilical vein EC (HUVEC) to hypoxia (1% O(2) for 4 h) followed by re-oxygenation (21% O(2) for 1 h-24 h). We observed transient expression of pro-inflammatory molecules (E-selectin, VCAM-1 and IL-8) and sustained expression of A20 in HUVEC exposed to hypoxia/re-oxygenation. The effect of A20 on endothelial responses to hypoxia/re-oxygenation was assessed. We observed that pre-treatment of HUVEC with an adenovirus containing A20 (Ad-A20) suppressed activation of NF-kappaB and induction of pro-inflammatory molecules by hypoxia/re-oxygenation, whereas a control adenovirus had little or no effect. Thus the induction of A20 may form a negative feedback loop in pro-inflammatory signalling in cells exposed to hypoxia/re-oxygenation. To validate our cell culture experiments we examined the role of A20 in renal responses to I/R. We observed that A20 was induced in rat kidneys exposed to I/R. Moreover, pre-treatment of animals with Ad-A20 significantly reduced acute tubular necrosis, renal expression of VCAM-1 and NF-kappaB activation in response to I/R, whereas pre-treatment with control adenovirus did not. Our observations suggest that A20 maintains physiological homeostasis in kidneys exposed to I/R by protecting them from inflammation and injury.
authors.affiliation: Department of Nephrology, Technische Universität München, Klinikum rechts der Isar, Munich, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Lutz
authors.forename: Le A
authors.initials: le A
authors.lastname: Luong
authors.forename: Matthias
authors.initials: M
authors.lastname: Strobl
authors.forename: Meihong
authors.initials: M
authors.lastname: Deng
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Martina
authors.initials: M
authors.lastname: Anton
authors.forename: Mustafa
authors.initials: M
authors.lastname: Zakkar
authors.forename: Karine
authors.initials: K
authors.lastname: Enesa
authors.forename: Hera
authors.initials: H
authors.lastname: Chaudhury
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Marcus
authors.initials: M
authors.lastname: Baumann
authors.forename: Joseph
authors.initials: J
authors.lastname: Boyle
authors.forename: Sarah
authors.initials: S
authors.lastname: Harten
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Charles
authors.initials: C
authors.lastname: Pusey
authors.forename: Uwe
authors.initials: U
authors.lastname: Heemann
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology*; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D007668:Kidney / Q000187:drug effects / Q000276:immunology*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000276:immunology* / Q000517:prevention & control*; D014162:Transfection; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D014409:Tumor Necrosis Factor-alpha; C076529:TNFAIP3 protein, human; C000602677:TNFAIP3 protein, rat; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3