Heme oxygenase-1 (HO-1) is an antioxidant enzyme and is believed to protect against oxidative stress-induced tissue injury. Renal ischemia-reperfusion (IR) injury seems at least in part to be caused by the oxidative stress. The aim of this study was to improve the renal IR injury by clinically available means. When littermate hemolysate was intravenously administered into rats, HO-1 was markedly induced in the kidneys. To investigate whether prior induction of HO-1 by the hemolysate injection ameliorates the subsequent renal IR injury, we assessed the levels of blood urea nitrogen (BUN) and serum creatinine (SCr), markers for renal injury, in rats with 45 min of ischemia followed by 18 h of reperfusion. To avoid the nephrotoxicity induced by hemolysate, small but effective amounts of hemolysate was injected into rats at 48 h prior to the ischemia. The levels of BUN and SCr values were significantly improved as compared to the rats with renal IR injury alone. Administration of HO inhibitor abolished the efficacy of hemolysate pretreatment. Our findings indicated that the prior induction of HO-1 by treatment of littermate hemolysate ameliorated the subsequent renal IR injury. Prior injection of self-hemolysate would be clinically useful for the protection against the renal IR injury induced by kidney transplantation and kidney surgery without immunological and infectious problems.

Keywords:
Heme oxygenase-1, Acute renal injury, Ischemia and reperfusion injury, Oxidative stress
1.
Maines MD, Trakshel GM, Kutty RK: Characterization of two constitutive forms of rat liver oxygenase: Only one molecular species of the enzyme is inducible. J Biol Chem 1986;261:411–419.
2.
Maines MD: Heme oxygenase: Function, multiplicity, regulatory mechanisms and clinical application. FASEB J 1988;2:2557–2568.
3.
Stocker R, Glazer AN, Ames BN: Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci USA 1987;84:5918–5922.
4.
Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN: Bilirubin is an antioxidant of possible physiological importance. Science 1987;235:1043–1046.
5.
Dore S, Takahashi M, Ferris CD, Zakhary R, Hester LD, Guastella D, Snyder SH: Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc Natl Acad Sci USA 1999;96:2445–2450.
6.
McCoubrey WKJ, Ewing JF, Maines MD: Human heme oxygenase-2: Characterization and expression of a full-length cDNA and evidence suggesting that the two HO-2 transcripts may differ by choice of polyadenylation signal. Arch Biochem Biophys 1992;295:13–20.
7.
Shibahara S, Yoshizawa M, Suzuki H, Takeda K, Meguro K, Endo K: Functional analysis of cDNAs for two types of human heme oxygenase and evidence for their separate regulation. J Biochem (Tokyo) 1993;113:214–218.
8.
Maines MD, Kappas A: Metals as regulators of heme metabolism. Science 1977;198:1215–1221
9.
Abraham NG, Lin JH, Schwartzman ML, Levere RD, Shibahara S: The physiological significance of heme oxygenase. Int J Biochem 1988;20:543–558.
10.
Horikawa S, Ito K, Ikeda S, Shibata T, Ishizuka S, Yano T, Hagiwara K, Ozasa H, Katsuyama I: Induction of heme oxygenase-1 in toxic renal injury: Mercuric chloride-induced acute renal failure in rat. Toxicol Lett 1998;94:57–64.
11.
Yoneya R, Ozasa H, Nagashima Y, Koike Y, Teraoka H, Hagiwara K, Horikawa S: Hemin pretreatment ameliorates aspects of the nephropathy induced by mercuric chloride in the rat. Toxicol Lett 2000;116:223–229.
12.
Applegate LA, Luscher P, Tyrrell RM: Induction of heme oxygenase: A general response to oxidant stress in cultured mammalian cells. Cancer Res 1991;51:974–978.
13.
Ryter SW, Tyrrell RM: The heme synthesis and degradation pathways: Role in oxidant sensitivity: Heme oxygenase has both pro- and antioxidant properties. Free Radic Biol Med 2000;28:289–309.
14.
Bonventre JV: Mechanisms of ischemic acute renal failure. Kidney Int 1993;43:1160–1178.
15.
Paller MS, Jacob HS: Cytochrome P-450 mediates tissue-damaging hydroxyl radical formation during reoxygenation of the kidney. Proc Natl Acad Sci USA 1994;91:7002–7006.
16.
Paller MS, Hoidal JR, Ferris TF: Oxygen free radicals in ischemic acute renal failure in the rat. J Clin Invest 1984:74:1156–1164.
17.
Ratych RE, Bulkley GB: Free-radical-mediated postischemic reperfusion injury in the kidney. Free Rad Biol Med 1986;2:311–319.
18.
Baker GL, Corry RJ, Autor AP: Oxygen free radical induced damage in kidneys subjected to warm ischemia and reperfusion: Protective effect of superoxide dismutase. Ann Surg 1985;202:628–641.
19.
Shimizu H, Takahashi T, Suzuki T, Yamasaki A, Fujiwara T, Odaka Y, Hirakawa M, Fujita H, Akagi R: Protective effect of heme oxygenase induction in ischemic acute renal failure. Crit Care Med 2000;28:809–817.
20.
Drummond GS, Galbraith RA, Sardana MK, Kappas A: Reduction of C2 and C4 vinyl groups of Sn-protoporphyrin to form Sn-mesoporphyrin markedly enhances the ability of the metalloporphyrin to inhibit in vivo heme catabolism. Arch Biochem Biophys 1987;255:64–74.
21.
Valaes T, Petmezaki S, Henschke C, Drummond GS, Kappas A: Control of jaundice in preterm newborns by an inhibitor of bilirubin production: Studies with tin-mesoporphyrin. Pediatrics 1994;93:1–11.
22.
Nath KA, Balla G, Vercellotti GM, Balla J, Jacob HS, Levitt MD, Rosenberg ME: Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest 1992;90:267–270.
23.
Vogt BA, Shanley TP, Croatt A, Alam J, Johnson KJ, Nath KA: Glomerular inflammation induces resistance to tubular injury in the rat: A novel form of acquired, heme oxygenase-dependent resistance to renal injury. J Clin Invest 1996;98:2139–2145.
24.
Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124–1136.
25.
Peralta C, Closa D, Hotter G, Gelpi E, Prats N, Rosello-Catafau J: Liver ischemic preconditioning is mediated by the inhibitory action of nitric oxide on endothelin. Biochem Biophys Res Commun 1996;229:264–270.
26.
Cochrane J, Williams BT, Banerjee A, Harken AH, Burke TJ, Cairns CB, Shapiro JI: Ischemic preconditioning attenuates functional, metabolic, and morphologic injury from ischemic acute renal failure in the rat. Ren Fail 1999;21:135–145.
27.
Kume M, Yamamoto Y, Saad S, Gomi T, Kimoto S, Shimabukuro T, Yagi T, Nakagami M, Takada Y, Morimoto T, Yamaoka Y: Ischemic preconditioning of the liver in rats: Implications of heat shock protein induction to increase tolerance of ischemia-reperfusion injury. J Lab Clin Med 1996;128:251–258.
28.
Yamagami K, Yamamoto Y, Kume M, Kimoto S, Yamamoto H, Ozaki N, Yamamoto M, Shimahara Y, Toyokuni S, Yamaoka Y: Heat shock preconditioning ameliorates liver injury following normothermic ischemia-reperfusion in steatotic rat livers. J Surg Res 1998;79:47–53.
29.
Balla J, Jacob HS, Balla G, Nath K, Eaton JW, Vercellotti GM: Endothelial-cell heme uptake from heme proteins: Induction of sensitization and desensitization to oxidant damage. Proc Natl Acad Sci USA 1993;90:9285–9289.
30.
Zager RA, Burkhart KM, Conrad DS, Gmur DJ: Iron, heme oxygenase, and glutathione: Effects on myohemoglobinuric proximal tubular injury. Kidney Int 1995;48:1624–1634.
31.
Stocker R: Induction of haem oxygenase as a defense against oxidative stress. Free Rad Res Commun 1990;9:101–112.
32.
Vincent SH: Oxidative effects of heme and porphyrins on proteins and lipids. Semin Hematol 1989;26:105–113.
© 2002 S. Karger AG, Basel
2002
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.