The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo

KA Nath, JJ Haggard, AJ Croatt, JP Grande… - The American journal of …, 2000 - Elsevier
KA Nath, JJ Haggard, AJ Croatt, JP Grande, KD Poss, J Alam
The American journal of pathology, 2000Elsevier
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 …
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.
Elsevier