Lutz, J and Luong, LA and Strobl, M and Deng, MH and Huang, H and Anton, M and Zakkar, M and Enesa, K and Chaudhury, H and Haskard, DO and Baumann, M and Boyle, J and Harten, S and Maxwell, PH and Pusey, C and Heemann, U and Evans, PC (2008) The A20 gene protects kidneys from ischaemia/reperfusion injury by suppressing pro-inflammatory activation. J MOL MED-JMM , 86 (12) 1329 - 1339. 10.1007/s00109-008-0405-4.
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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-kappa B transcription factors which induce pro-inflammatory molecules in endothelial cells (EC). We examined whether A20, a negative regulator of NF-kappa B, 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-kappa B 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-kappa B 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.
|Title:||The A20 gene protects kidneys from ischaemia/reperfusion injury by suppressing pro-inflammatory activation|
|Keywords:||Endothelial cells, Renal, Hypoxia, re-oxygenation, Ischaemia, reperfusion, A20, NF-kappa B, Ischaemia, Kidney, Gene transfer, NF-KAPPA-B, TUMOR-NECROSIS-FACTOR, ISCHEMIA-REPERFUSION INJURY, DELAYED GRAFT FUNCTION, ZINC-FINGER PROTEIN, ISCHEMIA/REPERFUSION INJURY, ENDOTHELIAL-CELLS, MYOCARDIAL-INFARCTION, IN-VIVO, EXPRESSION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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