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

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 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. Heme oxygenase (HO) is the rate limiting enzyme in the degradation of heme.

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

“…This effect is in agreement with results that have been described by others. Nath et al (2,41,42) showed that a decrease in HO activity predisposed rats to marked tubular interstitial inflammation and mortality after repetitive dosing with hemoglobin. It is also in agreement with those who have studied HO-2 deficiency in the heart and lung (43).…”

“…These are attributed to the capacity of HO to degrade heme that is released from oxidant-destabilized heme proteins (2) and to the production of bilirubin, which has potent antioxidant effects (3), as well as the generation of the vasodilator gas carbon monoxide (CO) (1). HO-1 and HO-2, the inducible and constitutive HO forms, respectively, play an important role in maintaining renal blood flow (4).…”

Physiology and Pathophysiology of Heme

“…In complementary studies, the prior induction of HO-1 by "conditioning" the kidney by exposure to small amounts of hemoglobin (9), endotoxin (37), or nephrotoxic serum (38) also conferred protection against glycerol-induced acute renal failure, as did hyperbilirubinemia, the latter achieved by bile duct ligation (39). In addition, mutant mice that are unable to express HO-1 exhibit markedly increased sensitivity to heme proteins as evidenced by heightened renal injury, accumulation of heme, and increased mortality when subjected to the glycerol model or hemoglobin (40).…”

Blood labile iron effect on nitrosative stress development under rat experimental rhabdomyolysis

“…Перша розглядається як стресовий протеїн, синтез якого індукується у відповідь на різні стрес-фактори та забезпечує захист клітин від ушкоджуючої дії вільного гему. Раніше встановлено важливість індукції ГО-1 за умови рабдоміолізу, стимульованого гліцерином [5]. Так, у нокаут-них по гену даного ізоферменту тварин на експериментальній моделі рабдоміолізу набувають розвитку симптоми ниркової недостатності зі 100%-ною летальністю.…”

“…Відомо, що індукція гемоксидази є одним із основних механізмів деградації гемопротеїнів та перешкоджає розвитку тканинних ушкоджень у нирках при рабдо-міолізі у щурів [2,4] та при ін'єкції гемоглобіну мишам [5]. У процесі інтенсивного вивільнення гему з цих протеїнів можливе утворення вільного феруму.…”