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      A Comparative Study of the Effects of Hemin and Bilirubin on Bilateral Renal Ischemia Reperfusion Injury

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          Background/Aims: The aim of this study was to determine the effects of hemin, a heme oxygenase-1 inducer, and bilirubin on renal ischemia-reperfusion (I-R) injury. Methods: 40 Wistar-Albino rats were allocated into six groups as follows: sham (S), bilirubin (B), hemin (H), ischemia/reperfusion (IR), IR + bilirubin (IRB) and IR + hemin (IRH). Conjugated bilirubin (20 mg·kg<sup>–1</sup> i.v.) was given to rats in groups B and IRB, and hemin (50 mg·kg<sup>–1</sup> i.p.) was given to rats in groups H and IRH just prior to reperfusion. Renal I-R was achieved by occluding the renal arteries bilaterally for 50 min. Following 6 h of reperfusion, blood was drawn to study BUN, creatinine and bilirubin, and tissue samples were harvested to determine the renal malonyldialdehyde and heme oxygenase-1 levels, and for histopathologic grading. Results: BUN, creatinine and malonyldialdehyde levels in group IRH were similar to controls whereas the results of groups IR and IRB were significantly higher (p < 0.01). There was a grade 2 damage in all I-R groups. Conclusion: This study showed the preventive effect of hemin on renal ischemia reperfusion injury. Administration of exogenous bilirubin did not prevent the I-R injury.

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          Most cited references 11

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          Protective effect of heme oxygenase induction in ischemic acute renal failure.

          To examine the role of heme oxygenase-1 (HO-1) induction in the recovery of renal function in rats with ischemic acute renal failure. Randomized, masked, controlled animal study. University-based animal research facility. Sprague-Dawley male rats, weighing 200-250 g. Anesthetized rats were subjected to bilateral flank incisions, and the right kidney was removed. Renal ischemia was performed by left renal microvascular clamping, followed by reflow of the blood. Ischemia of the kidney in the uninephrectomized rat significantly induced HO-1 messenger RNA, protein, and enzyme activity, reaching a maximum at 6 hrs, which was mediated in part through an increase in microsomal heme concentration. Heat shock protein 70 was induced extremely rapidly, reaching a maximum at 1 hr, suggesting that HO-1 and heat shock protein 70 gene expression are regulated separately. Inhibition of HO activity by tin mesoporphyrin, which resulted in an increase in microsomal heme concentration, significantly exacerbated renal function, as judged by the sustained increase in serum creatinine concentration and extensive tubular epithelial cell injuries. In contrast, animals that did not receive tin mesoporphyrin showed normal creatinine concentration and microsomal heme concentration 24 hrs after reperfusion, as well as restoration of abnormal renal histology. These findings indicate that the expression of HO-1 in the ischemic kidney may be critical in the recovery of renal cell function in this animal model. These findings also suggest that H0-1 induction may play an important role in conferring protection on renal cells from oxidative damage caused by heme.
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            Heme oxygenase in diabetes-induced oxidative stress in the heart.

            Diabetic cardiomyopathy is responsible for substantial morbidity and mortality in the diabetic population. Increased oxidative stress has been associated with the pathogenesis of chronic diabetic complications including cardiomyopathy. Multiple biochemical mechanisms have been proposed to increase oxidative stress in diabetes. The present study was aimed at elucidating the role of a potent oxidative and cellular stress-responsive system, the heme oxygenase (HO) system, in the heart in diabetes. Streptozotocin-induced diabetic rats were treated with a potent inhibitor of HO system, tin protoporphyrin IX (SnPPIX, 50 micromol/kg/d), and were compared with untreated diabetic and non-diabetic animals. All treatments began at the onset of diabetes, 48 h after injection of streptozotocin along with the confirmation of hyperglycemia. Animals were euthanized after 1 week and 1 month of treatment, and heart tissues were harvested. Frozen tissues were subjected to HO-1 and HO-2 mRNA expression by real-time RT-PCR and HO activity determination. Paraffin-embedded tissue sections were used for immunohistochemical analysis of HO-1 and HO-2. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) stain, a sensitive and specific marker of DNA damage, was preformed to assess damage induced by oxidative stress. In addition, tissue sections were subjected to histochemical analysis for iron. We further examined non-diabetic animals treated with a direct HO agonist, hemin (50 mg/kg/d). A possible relationship between the HO and the nitric oxide (NO) pathways was also considered by studying the mRNA levels of endothelial nitric oxide synthase (NOS) and inducible NOS, and by measuring the amount of NOS products. Our results demonstrate no significant alterations of the HO system following 1 week of diabetes. However, 1 month of diabetes caused increased oxidative stress as demonstrated by higher levels of 8-OHdG-positive cardiomyocytes (80% positive as compared to 11.25% in controls), in association with increased HO isozyme mRNA (2.7-fold increase as compared to controls) and protein expression, and augmented HO activity (759.3 as compared to 312.3 pmol BR/h/mg protein in controls). Diabetic rats further demonstrated increased number of cardiomyocytes with stainable iron. SnPPIX treatment resulted in reduced number of 8-OHdG-positive cardiomyocytes (19.5% as compared to 80% in diabetics) in parallel with reduced HO activity (569.7 as compared to 759.3 pmol BR/h/mg protein in diabetics). Non-diabetic rats treated with HO-agonist hemin exhibited abnormalities similar to diabetic rats. Our results provide the first direct demonstration that diabetes-induced oxidative stress in the heart is, in part, due to upregulated HO expression and activity. These results provide evidence of pro-oxidant activity of HO in the heart in diabetes, which could be mediated by increased redox-active iron.
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              Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1


                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                April 2006
                09 December 2005
                : 103
                : 1
                : e1-e5
                Departments of aPediatric Surgery, bNephrology, cBiochemistry, dPathology and eTransplantation Unit, Faculty of Medicine, Gazi University, and fDepartment of Pediatric Surgery, Faculty of Medicine, Kocaeli University, Ankara, Turkey
                90113 Nephron Exp Nephrol 2006;103:e1–e5
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 7, References: 21, Pages: 1
                Self URI (application/pdf):
                Original Paper

                Cardiovascular Medicine, Nephrology

                Heme oxygenase, Hemin, Ischemia-reperfusion injury, Kidney, Bilirubin


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