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, Kenneth D. Poss, Jawed Alam

Research output: Contribution to journalArticlepeer-review

221 Scopus citations

Abstract

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 con-tent 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.

Original languageEnglish (US)
Pages (from-to)1527-1535
Number of pages9
JournalAmerican Journal of Pathology
Volume156
Issue number5
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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