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 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.
Nath
K A
KA
Nephrology Research Unit, Mayo Clinic/Foundation, Rochester, Minnesota 55905, USA. nath.karl@mayo.edu
Haggard
J J
JJ
Croatt
A J
AJ
Grande
J P
JP
Poss
K D
KD
Alam
J
J
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D003404:Creatinine / Q000097:blood; D005260:Female; D005990:Glycerol / Q000008:administration & dosage / Q000009:adverse effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006420:Hemeproteins / Q000378:metabolism* / Q000494:pharmacology; D006454:Hemoglobins / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007677:Kidney Function Tests; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016019:Survival Analysis; D015996:Survival Rate
D006420:Hemeproteins; D006454:Hemoglobins; D008565:Membrane Proteins; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D005990:Glycerol