期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 74, 期 -, 页码 263-273出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2014.07.003
关键词
C1 inhibitor; Complement system; NOX-2; NOX-4; Oxidative stress; Renal ischemia-reperfusion injury; Renal transplantation; Free radicals
资金
- Pharming Group NV, Leiden, The Netherlands
- Ministero della Salute (Ricerca Finalizzata and Giovani Ricercatori)
NADPH oxidase plays a central role in mediating oxidative stress during heart, liver, and lung ischemia/reperfusion injury, but limited information is available about NADPH oxidase in renal ischemia/reperfusion injury. Our aim was to investigate the activation of NADPH oxidase in a swine model of renal ischemia/reperfusion damage. We induced renal ischemia/reperfusion in 10 pigs, treating 5 of them with human recombinant C1 inhibitor, and we collected kidney biopsies before ischemia and 15, 30, and 60 mm after reperfusion. Ischemia/reperfusion induced a significant increase in NADPH oxidase 4 (NOX-4) expression at the tubular level, an upregulation of NOX-2 expression in infiltrating monocytes and myeloid dendritic cells, and 8-oxo-7,8-dihydro-2'-deoxyguanosine synthesis along with a marked upregulation of NADPH-dependent superoxide generation. This burden of oxidative stress was associated with an increase in tubular and interstitial expression of the myofibroblast marker alpha-smooth muscle actin (alpha-SMA). Interestingly, NOX-4 and NOX-2 expression and the overall NADPH oxidase activity as well as alpha-SMA expression and 8-oxo-7,8-dihydro-2'-deoxyguanosine synthesis were strongly reduced in Cl-inhibitor-treated animals. In vitro, when we incubated tubular cells with the anaphylotoxin C3a, we observed an enhanced NADPH oxidase activity and alpha-SMA protein expression, which were both abolished by NOX-4 silencing. In conclusion, our findings suggest that NADPH oxidase is activated during ischemia/reperfusion in a complement-dependent manner and may play a potential role in the pathogenesis of progressive renal damage in this setting. (C) 2014 Elsevier Inc. All rights reserved.
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