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

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 mech anism is the degradation of heme released from destabilized. heme proteins. We demonstrate that HO-1 is a critical protectant against acute heme prote in-induced toxicity in vivo. In the glycerol model of heme protein toxicity -one characterized by myolysis, hemolysis, and kidney damage-HO-1 is rapidl y induced in the kidney of HO-1 +/+ mice as the latter sustain mild, revers ible renal insufficiency without mortality. In stark contrast, after this i nsult, HO-1 -/- mice exhibit fulminant, irreversible renal failure and 100% mortality; HO-1 -/- mice do not express HO-1, and evince an eightfold incr ement in kidney heme content as compared to HO-1 +/+ mice. We also demonstr ate directly the critical dependency on HO-1 in protecting against a specif ic heme protein, namely, hemoglobin: doses of hemoglobin which exert no nep hrotoxicity or mortality in HO-1 +/+ mice, however, precipitate rapidly dev eloping, acute renal failure and marked mortality in HO-1 -/- mice. We conc lude that the induction of HO-1 is an indispensable response in protecting against acute heme protein toxicity in vivo.