Pharmacological induction of heme oxygenase-1 inhibits iNOS and oxidative stress in renal ischemia-reperfusion injury.
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.
Li Volti
G
G
Department of Biological Chemistry, University of Catania, Catania, Italy. livolti@unict.it
Sorrenti
V
V
Murabito
P
P
Galvano
F
F
Veroux
M
M
Gullo
A
A
Acquaviva
R
R
Stacchiotti
A
A
Bonomini
F
F
Vanella
L
L
Di Giacomo
C
C
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D007527:Isoenzymes / Q000096:biosynthesis; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000503:physiopathology*; D013438:Sulfhydryl Compounds / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009566:Nitrates; D009573:Nitrites; D013438:Sulfhydryl Compounds; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1