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 min 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 α-smooth muscle actin (α-SMA). Interestingly, NOX-4 and NOX-2 expression and the overall NADPH oxidase activity as well as α-SMA expression and 8-oxo-7,8-dihydro-2′-deoxyguanosine synthesis were strongly reduced in C1-inhibitor-treated animals. In vitro, when we incubated tubular cells with the anaphylotoxin C3a, we observed an enhanced NADPH oxidase activity and α-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. © 2014 Elsevier Inc.

Simone, S., Rascio, F., Castellano, G., Divella, C., Chieti, A., Ditonno, P., Battaglia, M., Crovace, A., Staffieri, F., Oortwijn, B., Stallone, G., Gesualdo, L., Pertosa, G., Grandaliano, G., Complement-dependent NADPH oxidase enzyme activation in renal ischemia/reperfusion injury, <<FREE RADICAL BIOLOGY & MEDICINE>>, 2014; 74 (2014): 263-273. [doi:10.1016/j.freeradbiomed.2014.07.003] [http://hdl.handle.net/10807/196980]

Complement-dependent NADPH oxidase enzyme activation in renal ischemia/reperfusion injury

Grandaliano, G.
2014

Abstract

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 min 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 α-smooth muscle actin (α-SMA). Interestingly, NOX-4 and NOX-2 expression and the overall NADPH oxidase activity as well as α-SMA expression and 8-oxo-7,8-dihydro-2′-deoxyguanosine synthesis were strongly reduced in C1-inhibitor-treated animals. In vitro, when we incubated tubular cells with the anaphylotoxin C3a, we observed an enhanced NADPH oxidase activity and α-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. © 2014 Elsevier Inc.
2014
Inglese
Simone, S., Rascio, F., Castellano, G., Divella, C., Chieti, A., Ditonno, P., Battaglia, M., Crovace, A., Staffieri, F., Oortwijn, B., Stallone, G., Gesualdo, L., Pertosa, G., Grandaliano, G., Complement-dependent NADPH oxidase enzyme activation in renal ischemia/reperfusion injury, <<FREE RADICAL BIOLOGY & MEDICINE>>, 2014; 74 (2014): 263-273. [doi:10.1016/j.freeradbiomed.2014.07.003] [http://hdl.handle.net/10807/196980]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/196980
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