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J Biol Chem, Vol. 273, Issue 48, 31731-31737, November 27, 1998

A Causative Role for Redox Cycling of Myoglobin and Its Inhibition by Alkalinization in the Pathogenesis and Treatment of Rhabdomyolysis-induced Renal Failure

Kevin P. MooreDagger , Steve G. HoltDagger , Rakesh P. Patel, Dimitri A. Svistunenkoparallel , William Zackert**, David GoodierDagger , Brandon. J. Reederparallel , Martine ClozelDagger Dagger , Radhi AnandDagger , Christopher E. Cooperparallel , Jason D. Morrow**, Michael T. Wilsonparallel , Victor Darley-Usmar, and L. Jackson Roberts II**

From the Dagger  Joint Department of Medicine, Royal Free and University College Medical School, London NW3 2QG, United Kingdom, the  Center for Free Radical Biology and Department of Pathology, Molecular and Cellular Division, University of Alabama, Birmingham, Alabama 35243, the ** Departments of Pharmacology and Medicine, Vanderbilt Medical Center, Nashville, Tennessee 37232, Dagger Dagger  Preclinical Research, Hoffmann-La Roche, Basel 4070, Switzerland, and the parallel  Department of Biological Sciences, University of Essex, Colchester, Essex CO4 3SQ, United Kingdom

Muscle injury (rhabdomyolysis) and subsequent deposition of myoglobin in the kidney causes renal vasoconstriction and renal failure. We tested the hypothesis that myoglobin induces oxidant injury to the kidney and the formation of F2-isoprostanes, potent renal vasoconstrictors formed during lipid peroxidation. In low density lipoprotein (LDL), myoglobin induced a 30-fold increase in the formation of F2-isoprostanes by a mechanism involving redox cycling between ferric and ferryl forms of myoglobin. In an animal model of rhabdomyolysis, urinary excretion of F2-isoprostanes increased by 7.3-fold compared with controls. Administration of alkali, a treatment for rhabdomyolysis, improved renal function and significantly reduced the urinary excretion of F2-isoprostanes by ~80%. EPR and UV spectroscopy demonstrated that myoglobin was deposited in the kidneys as the redox competent ferric myoglobin and that it's concentration was not decreased by alkalinization. Kinetic studies demonstrated that the reactivity of ferryl myoglobin, which is responsible for inducing lipid peroxidation, is markedly attenuated at alkaline pH. This was further supported by demonstrating that myoglobin-induced oxidation of LDL was inhibited at alkaline pH. These data strongly support a causative role for oxidative injury in the renal failure of rhabdomyolysis and suggest that the protective effect of alkalinization may be attributed to inhibition of myoglobin-induced lipid peroxidation.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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