Submitted on June 16, 2008
Revised on January 28, 2009
Accepted on February 13, 2009
L-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats
Matthieu Legrand1*, Emre Almac2, Egbert G Mik3, Tanja Johannes4, Asl
Kandil5, Rick Bezemer6, Didier Payen, and Can Ince7
1 AMC
2 Academic Medical Center, Amsterdam, The Netherlands
3 Erasmus Medical Center, University of Rotterdam, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
4 University Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72074 Tuebingen, Germany
5 Department of Biology, Istanbul University, Faculty of Science, 34459, Vezneciler, Istanbul, Turkey.
6 Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
7 Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: m.legrand{at}libertysurf.fr.
Even though renal hypoxia is believed to play a pivotal role in the development of acute kidney injury, no study has specifically addressed the alterations in renal oxygenation in the early onset of renal ischemia/reperfusion (I/R). Renal oxygenation depends on a balance between oxygen supply and consumption, with the nitric oxide (NO) as a major regulator of microvascular oxygen supply and oxygen consumption. The aim of this study was to investigate whether I/R induces iNOS-dependent early changes in renal oxygenation and the potential benefit of inducible-NOS inhibitors on such alterations. Anesthetized Sprague-dawley rats underwent a 30 minutes supra-renal aortic clamping with or without either the non-selective nitric oxide synthase (NOS) inhibitor L-NAME or the selective iNOS inhibitor L-NIL. Cortical (CµPO2), and outer-medullary (MµPO2) microvascular oxygen pressure, renal oxygen delivery(DO2ren), renal oxygen consumption(VO2ren) and renal oxygen extraction(O2ER) were measured using oxygen-dependent quenching phosphorescence techniques throughout 2 hours of reperfusion. During reperfusion renal arterial resistance and oxygen shunting increased, whereas renal blood flow, CµPO2 and MµPO2(-70%,-42% and-42% respectively, p<0.05), VO2ren, and DO2ren (-70%, p<0.0001, and -28%, p<0.05) dropped. Whereas L-NAME further decreased DO2ren, VO2ren, CµPO2 and MµPO2 , and deteriorated renal function, L-NIL partially prevented the drop of DO2ren , µPO2 , increased O2ER , restored VO2ren, and prevented deterioration of renal function. Our results demonstrate that renal I/R induces early iNOS-dependent microvascular hypoxia in disrupting the balance between microvascular oxygen supply and renal oxygen consumption, while eNOS activity is compulsory for the maintenance of this balance. L-NIL can prevent ischemic-induced renal microvascular hypoxia.
