Pharmacological Induction of Heme Oxygenase-1 Inhibits iNOS and Oxidative Stress in Renal Ischemia-Reperfusion Injury

• Published in: Transplantation proceedings 2007-12, Vol.39 (10), p.2986-2991
• Main Authors: Li Volti, G, Sorrenti, V, Murabito, P, Galvano, F, Veroux, M, Gullo, A, Acquaviva, R, Stacchiotti, A, Bonomini, F, Vanella, L, Di Giacomo, C
• Format: Article
• Language: English
• Subjects: Animals; Cyclooxygenase Inhibitors - pharmacology; Disease Models, Animal; Enzyme Induction - drug effects; Heme Oxygenase-1 - biosynthesis; Isoenzymes - biosynthesis; Nitrates - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitrites - metabolism; Oxidative Stress - physiology; Rats; Renal Circulation; Reperfusion Injury - physiopathology; Sulfhydryl Compounds - metabolism; Surgery
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2007.09.047

Abstract Nitric oxide (NO), produced by nitric oxide synthase, is implicated in the pathophysiology of renal ischemia/reperfusion (I/R) injury. This study sought to elucidate the impact of pharmacological induction of heme oxygenase-1 (HO-1) on renal I/R injury. Rats were subjected to 45 minutes of renal ischemia followed by various times of reperfusion (30 minutes, 1 hour, or 3 hours). Plasma from sacrificed rats was obtained, and the kidneys processed for the expression of iNOS, cleaved caspase-3, p38MAPK and for immunohistochemical analysis. Furthermore, we determined renal and plasma levels of lipid hydroperoxides, total thiol groups, and plasmatic NO2− /NO3− formation. Our results showed a time-dependent increase in iNOS expression, which was also confirmed by increased plasma formation of NO2− /NO3− . Interestingly, this effect was reversed by pretreatment (12 hours) with SnCl2 , a potent and specific inducer of renal HO-1 expression and activity, or by intraperitoneal injection of biliverdin (10 mg/kg). Furthermore, we observed a concomitant reduction in plasma and renal LOOH formation, a normalization of renal total thiol content, a reduction of caspase-3-mediated apoptosis, and a significant increase in p38MAPK phosphoration. Taken together, these results suggested that HO-1 and its byproduct biliverdin play major roles in the pathophysiological cascade leading to renal I/R injury.