A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure

被引:215
作者
Moore, KP
Holt, SG
Patel, RP
Svistunenko, DA
Zackert, W
Goodier, D
Reeder, BJ
Clozel, M
Anand, R
Cooper, CE
Morrow, JD
Wilson, MT
Darley-Usmar, V
Roberts, LJ II
机构
[1] UCL Royal Free & Univ Coll, Sch Med, Joint Dept Med, London NW3 2QG, England
[2] Univ Alabama Birmingham, Ctr Free Rad Biol, Birmingham, AL 35243 USA
[3] Univ Alabama Birmingham, Dept Pathol, Mol & Cellular Div, Birmingham, AL 35243 USA
[4] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA
[5] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
[6] Hoffmann La Roche AG, Preclin Res, CH-4070 Basel, Switzerland
[7] Univ Essex, Dept Biol Sci, Colchester CO4 3SQ, Essex, England
关键词
D O I
10.1074/jbc.273.48.31731
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 F-2-isoprostanes, potent renal vasoeonstrictors formed during lipid peroxidation. In low density lipoprotein (LDL), myoglobin induced a 30-fold increase in the formation of F-2-isoprostanes by a mechanism involving redox cycling between ferric and ferryl forms of myoglobin, In an animal model of rhabdomyolysis, urinary excretion of F-2-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 F-2-isoprostanes by similar to 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.
引用
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页码:31731 / 31737
页数:7
相关论文
共 42 条
[21]  
MAREE A, 1994, NEPHROL DIAL TRANSPL, V9, P78
[22]   FORMATION OF F-2-ISOPROSTANES DURING OXIDATION OF HUMAN LOW-DENSITY-LIPOPROTEIN AND PLASMA BY PEROXYNITRITE [J].
MOORE, KP ;
DARLEYUSMAR, V ;
MORROW, J ;
ROBERTS, LJ .
CIRCULATION RESEARCH, 1995, 77 (02) :335-341
[23]   NON-CYCLOOXYGENASE-DERIVED PROSTANOIDS (F2-ISOPROSTANES) ARE FORMED INSITU ON PHOSPHOLIPIDS [J].
MORROW, JD ;
AWAD, JA ;
BOSS, HJ ;
BLAIR, IA ;
ROBERTS, LJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (22) :10721-10725
[24]   A SERIES OF PROSTAGLANDIN-F2-LIKE COMPOUNDS ARE PRODUCED INVIVO IN HUMANS BY A NONCYCLOOXYGENASE, FREE RADICAL-CATALYZED MECHANISM [J].
MORROW, JD ;
HILL, KE ;
BURK, RF ;
NAMMOUR, TM ;
BADR, KF ;
ROBERTS, LJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (23) :9383-9387
[25]  
MORROW JD, 1994, J BIOL CHEM, V269, P4317
[26]  
MORROW JD, 1994, METHOD ENZYMOL, V233, P163
[27]  
NATH KA, 1994, LAB INVEST, V71, P209
[28]   HEMOGLOBIN-INDUCED AND MYOGLOBIN-INDUCED ACUTE RENAL-FAILURE IN RATS - ROLE OF IRON IN NEPHROTOXICITY [J].
PALLER, MS .
AMERICAN JOURNAL OF PHYSIOLOGY, 1988, 255 (03) :F539-F544
[29]   Redox cycling of human methaemoglobin by H2O2 yields persistent ferryl iron and protein based radicals [J].
Patel, RP ;
Svistunenko, DA ;
DarleyUsmar, VM ;
Symons, MCR ;
Wilson, MT .
FREE RADICAL RESEARCH, 1996, 25 (02) :117-123
[30]  
Patel RP, 1996, J LIPID RES, V37, P2361