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(American Journal of Pathology. 2000;156:1527-1535.)
© 2000 American Society for Investigative Pathology

Regular Articles

The Indispensability of Heme Oxygenase-1 in Protecting against Acute Heme Protein-Induced Toxicity in Vivo

Karl A. Nath*, Jill J. Haggard*, Anthony J. Croatt*, Joseph P. Grande{dagger}, Kenneth D. Poss{ddagger} and Jawed Alam§

From the Nephrology Research Unit*
and the Department of Pathology,{dagger}
Mayo Clinic/Foundation, Rochester, Minnesota; the Center for Cancer Research,{ddagger}
Massachusetts Institute of Technology, Cambridge, Massachusetts; and the Department of Molecular Genetics,§
Alton Ochsner Medical Foundation, New Orleans, Louisiana

Heme oxygenase (HO) is the rate limiting enzyme in the degradation of heme, and its isozyme, HO-1, may protect against tissue injury. One posited mechanism is the degradation of heme released from destabilized heme proteins. We demonstrate that HO-1 is a critical protectant against acute heme protein-induced toxicity in vivo. In the glycerol model of heme protein toxicity—one characterized by myolysis, hemolysis, and kidney damage—HO-1 is rapidly induced in the kidney of HO-1 +/+ mice as the latter sustain mild, reversible renal insufficiency without mortality. In stark contrast, after this insult, HO-1 -/- mice exhibit fulminant, irreversible renal failure and 100% mortality; HO-1 -/- mice do not express HO-1, and evince an eightfold increment in kidney heme content as compared to HO-1 +/+ mice. We also demonstrate directly the critical dependency on HO-1 in protecting against a specific heme protein, namely, hemoglobin: doses of hemoglobin which exert no nephrotoxicity or mortality in HO-1 +/+ mice, however, precipitate rapidly developing, acute renal failure and marked mortality in HO-1 -/- mice. We conclude that the induction of HO-1 is an indispensable response in protecting against acute heme protein toxicity in vivo.




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