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Regular Articles |
From the Nephrology Research Unit*
and the
Department of Pathology,
Mayo
Clinic/Foundation, Rochester, Minnesota; the Center for Cancer
Research,
Massachusetts Institute of
Technology, Cambridge, Massachusetts; and the Department of Molecular
Genetics,§
Alton Ochsner Medical Foundation,
New Orleans, Louisiana
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One posited, but primarily unsubstantiated, mechanism invoked for the cytoprotective effects of HO-1 in the setting of tissue injury centers on the degradation of heme released from intracellular heme proteins that are destabilized pari passu as cells are injured.1-3 The heme prosthetic group is widespread in cells as it is found in proteins that store or carry oxygen, cytochromes, and numerous enzymes involved in diverse aspects of cellular metabolism. Destabilization of heme proteins in injured cells may lead to the disengagement of heme from its linked protein moiety. The linkage of heme with a given protein moiety not only enables the functional activity of the specific heme protein, but also restrains free heme from exerting injurious effects. A large body of literature confirms the cytotoxicity of free heme,12-15 and indeed, there are clinical observations attesting to the marked nephrotoxicity of heme when the latter—used to induce remission in patients with acute intermittent porphyria—is inadvertently administered in inordinate doses.16 Heme is a lipophilic prooxidant that can impair lipid bilayers and organelles such as mitochondria and nuclei; heme can also destabilize the cytoskeleton; finally, heme can impair a number of enzymes.12-17 In injured cells, the recruitment of HO-1 may degrade heme released from intracellular heme proteins, thereby safeguarding against this mechanism of cytotoxicity.
Besides the removal of heme, the induction of HO-1 procures potentially cytoprotectant molecules such as ferritin, bilirubin, and carbon monoxide. Ferritin provides a storage site for iron,18 whereas bilirubin is a metabolite with recognized antioxidant properties.19,20 Carbon monoxide is a critical intracellular signaling molecule in neural tissue;10 additionally, carbon monoxide possesses vasodilatory, anti-inflammatory, and cytoprotectant properties.10,11,21,22 Thus, the salutary effects afforded by the induction of HO-1 may reside in the recruitment of biochemically diverse cytoprotective substances, in addition to the reduction in an intracellular toxicant.
Much of the literature demonstrating a protective effect of induced HO-1, however, relies on pharmacological approaches which may exert effects besides those involving HO-1;23-25 the availability of genetically engineered mice deficient in HO-1 provides an opportunity to examine the protective effects of induced HO-1 without the confounding actions of such pharmacological manipulations.6,8 Moreover, very few studies have examined whether the potential cytoprotective effects of HO-1 are derived from restraining the tissue buildup of heme; and these studies do not include heme protein-induced toxicity. We thus examined the requirement for HO-1 in protecting against heme proteins—a possible intracellular toxicant in injured tissue, and one common to insults in which HO-1 is induced—using mice deficient in HO-1 (HO-1 -/-) or wild-type mice (HO-1 +/+). We used a long-established, in vivo model of heme protein-induced tissue injury, the glycerol model, in which we examined the relative sensitivity of these mice to such injury. The intramuscular injection of hypertonic glycerol induces myolysis and hemolysis thereby exposing tissues, especially the kidney, to large amounts of myoglobin and hemoglobin;26,27 acute renal failure dominates this disease model and the analogous clinical syndromes, such as those caused by crush injuries and a host of nontraumatic and medical disorders.27 Using this model of heme protein-induced renal injury, as well as the direct examination of the nephrotoxicity of a specific heme protein (hemoglobin), we provide compelling evidence for the indispensability of HO-1 in protecting against heme protein-mediated injury in vivo.
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Materials and Methods |
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Homozygous HO-1 null mutants were generated by targeted disruption of the HO-1 gene as described by Poss and Tonegawa.28 Colonies of mice were maintained by breeding HO-1 -/- males with HO-1 +/- females. Offspring were genotyped at the time of weaning by using polymerase chain reaction to amplify the wild-type and mutant alleles of genomic DNA obtained from tail samples. HO-1 +/+ mice (wild type) were used as controls. The characteristics of HO-1 -/- mice, described previously,28 include slower rate of somatic growth as compared to HO-1 +/+ mice; and thus to ensure that HO-1 +/+ and HO-1 -/- mice received comparably severe glycerol-induced exposure to heme proteins, HO-1 -/- mice were matched in body weight to HO-1 +/+ mice, the mean age of the HO-1 -/- mice being 30 weeks whereas the mean age of the HO-1 +/+ mice was 20 weeks. Groups of HO-1 +/+ and HO-1 -/- mice comprised similar numbers of male and female mice. Such groups were used in the study of the relative effects of the glycerol model of heme protein toxicity and the relative effects of a specific heme protein, namely, hemoglobin.
In additional studies of the nephrotoxic actions of hemoglobin in HO-1 +/+ and HO-1 -/- mice, we examined the effects of hemoglobin in HO-1 +/+ and HO-1 -/- mice that were much younger (age, 7 to 10 weeks) than those previously used (age, 20 to 30 weeks). In these additional studies using HO-1 +/+ and HO-1 -/- mice in the age range 7 to 10 weeks, mean body weights of these mice were not significantly different (21.5 ± 1.5 g versus 22.7 ± 1.7 g, respectively; P = ns); the toxicity of a specific heme protein was thus further studied in younger mice similar in age and body weight.
The Glycerol Model of Heme Protein-Induced Injury
HO-1 +/+ and HO-1 -/- mice, deprived of water overnight for 16 hours but allowed free access to rodent chow, were anesthetized with ether, and then injected with 50% glycerol in water, 7.5 ml/kg, half of the dose injected into each anterior thigh muscle.26,29 In initial studies, the renal effects of intramuscular injections of 50% glycerol at two doses, 7.5 ml/kg and 10 ml/kg, were examined in C57BL/6 mice.
Hemoglobin-Induced Acute Renal Failure
HO-1 +/+ and HO-1 -/- mice were deprived of water for 16 hours but allowed free access to rodent chow. Mice were given two tail vein injections of mouse hemoglobin (Sigma Chemical Co., St. Louis, MO), each consisting of 90 mg/100 g mouse hemoglobin, and administered 1 hour apart.
Plasma Creatinine
Renal function was assessed by plasma creatinine concentrations; the latter were determined on plasma derived from tail vein blood samples and using a Beckman Creatinine Analyzer II (Beckman Instruments, Inc., Fullerton, CA).29
Heme Content and Plasma Hemoglobin Concentrations
Plasma hemoglobin concentrations were determined by the method of Winterbourn.30 Heme content of whole kidney homogenates was determined by the pyridine hemochromogen method.31,32
Lactate Dehydrogenase and Creatine Kinase Activities
Plasma lactate dehydrogenase (LDH) activity was measured by determining the rate of formation of NADH.17 Plasma creatine kinase activity was measured by a colorimetric method using a Sigma Diagnostics Creatine Phosphokinase kit (Sigma Chemical Co.).
Northern Analysis
RNA from kidneys was extracted using the Trizol method (Life Technologies, Inc., Gaithersburg, MD). Ten µg of total RNA from each sample were separated on an agarose gel and transferred to a nylon membrane. Membranes were hybridized overnight with a 32P-labeled mouse HO-1 cDNA probe. Autoradiograms were standardized, as previously described,33 by factoring the optical density of the message for HO-1 with the optical density of the 18S rRNA, the latter obtained on a negative of the ethidium bromide-stained nylon membrane.
Western Analysis and Immunohistochemical Staining
Western analysis was performed using a polyclonal HO-1 antibody (SPA-895, Stressgen, Victoria, BC, Canada).33 For immunohistochemical localization, tissue sections were fixed in 10% formalin and embedded in paraffin. Staining for HO-1 was performed using a polyclonal antibody (SPA-895, Stressgen) as the primary antibody, a horseradish peroxidase conjugated secondary antibody (R14745, Transduction Laboratories, Lexington, KY) and diaminobenzidine as substrate for localization.
Statistics
Results are expressed as means ± SEM, and are considered statistically significant for P < 0.05. For comparison between unpaired groups, the Student’s t-test or the Mann-Whitney test was used as appropriate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, the kidney mounts a robust response
consisting of the induction of HO-1 mRNA.
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After glycerol, however, alterations in renal function were
fundamentally different in HO-1 +/+ and HO-1 -/- mice (Figure 2)
. Although plasma creatinines were
identical before the administration of glycerol, the plasma creatinine
was markedly increased in HO-1 -/- mice by days 2 and 3 after the
administration of hypertonic glycerol, findings that demonstrate
greater deterioration in renal function in HO-1 -/- mice (Figure 2)
.
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,
right panel); such histological features were uncommon in HO-1 +/+ mice
in that only isolated tubules showed evidence of such tubular necrosis
(Figure 3
, left panel); no gross renal histological abnormalities were
present in either group not subjected to glycerol (data not shown). In
these mice in which renal histological studies were undertaken,
worsened renal function was again observed in the HO-1 -/- mice as
compared to HO-1 +/+ mice subjected to glycerol: serum creatinine
measurements on day 2 after glycerol were 0.9 ± 0.3
versus 2.7 ± 0.1 mg/dl, P < 0.005,
n = 6 in each group.
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. LDH is a ubiquitous
cytosolic enzyme, and its elevation in plasma indicates cellular
injury. Plasma LDH profiles in HO-1 +/+ and HO-1 -/- mice were
different: in HO-1 +/+ mice, plasma LDH levels acutely rose by 6 hours
but normalized by 48 hours; in contrast, HO-1-/- mice demonstrate a
progressive and sustained rise in LDH, and by 48 hours, these levels
were increased 30-fold greater than levels in HO-1 +/+ mice, indicating
massive tissue injury. Interestingly, HO-1-/- mice evinced minimally
elevated LDH levels even in the basal state, perhaps reflecting the
endogenous cytoprotective effects of HO-1 in unstressed mice.
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.
The induction of myolysis and hemolysis by hypertonic glycerol promptly
and prominently induced HO-1 mRNA and protein in the kidney in HO-1 +/+
mice; no such induction occurred in the HO-1 -/- mice (Figure 5
, a and b). The lack of induction of
HO-1 in the HO-1 -/- mice enhanced the accumulation of heme which
occurs in this model: the increment in kidney heme content in HO-1
-/- mice was increased some eightfold above that which occurred in
HO-1 +/+ mice (Figure 5c)
. The site of induction of HO-1 protein in the
kidney in HO-1 +/+ mice after the administration of glycerol localized,
primarily, to the proximal tubule (Figure 6)
.
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, a and b). In
stark contrast, hemoglobin so administered to HO-1 -/- mice led to
acute renal failure and 75% mortality (Figure 7
, a and b). Thus, heme
proteins per se are uniquely toxic in mice rendered deficient in HO-1.
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; however, in response to hemoglobin
(180 mg/100 g, as administered previously), fulminant nephrotoxicity
occurred in the HO-1 -/- mice in that the serum creatinine was some
ninefold higher one day after hemoglobin (Figure 8)
. Such renal
dysfunction was accompanied by widespread necrosis of tubular
epithelial cells and tubular cast formation in the kidney in HO-1 -/-
mice (Figure 9
, right panel);
histologically, the kidney appeared normal in HO-1 +/+ mice one day
after hemoglobin (Figure 9
, left panel). Thus, in HO-1 -/- mice at a
relatively young age at which phenotypic changes pertaining to body
weight and other parameters do not emerge, the vulnerability of the
kidney to heme proteins is again present.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We examined the sensitivity of HO-1 -/- mice to heme protein toxicity at multiple levels. Our initial studies used the glycerol model because this is a long-established and conventional method of studying the toxicity of heme proteins in vivo, especially with regards to their nephrotoxicity.27 From these studies we proceeded to question whether the sensitivity of HO-1 -/- mice to glycerol-induced, heme protein-instigated, injury would also occur in response to heme proteins per se; and indeed, a specific heme protein, hemoglobin, proved markedly injurious to HO-1 -/- mice when administered in dosages that were innoucous in HO-1 +/+ mice. Having confirmed that this sensitivity of HO-1 -/- mice occurs in a model of heme protein toxicity (glycerol) and in response to a particular heme protein (hemoglobin), we then questioned whether such effects would also occur in younger HO-1 -/- mice. The rationale for the use of much younger animals was to address any concerns related to differences in body weight that emerge as these mice age; additionally, such younger mice are free from the mild inflammatory changes which evolve in older HO-1 -/- mice.28 To this end, we thus used sufficiently young mice such that the HO-1 +/+ and HO-1 -/- groups were matched in body weight and age, and before the emergence of the previously described mild inflammatory changes.28 Once again, dosages of hemoglobin that exerted no effect on the kidney (as assessed by plasma creatinine and histology) in HO-1 +/+ mice, induced severe functional and structural damage to the kidney in HO-1 -/- mice.
That HO-1 -/- mice are compromised in their capacity to metabolize heme proteins is germane to the view that HO-1 is required in iron recycling.28 In these previous studies which examined HO-1 -/- mice in the chronic, unstressed state, increased tissue deposition of iron was noted,28 and it was suggested that HO-1 is involved in the homeostasis of iron as HO-1 serves to expel iron from cellular stores.28 However, neither did this latter study, nor any other available study, address whether the deficiency of HO-1 in mice would render them acutely vulnerable in vivo to increased amounts of heme, the substrate that readily induces HO-1 and incriminated as an endogenous toxicant released from intracellular heme proteins in states of oxidant stress. This question is relevant not only from the pathobiology of oxidant injury but also from the clinical standpoint because tissues are exposed to large amounts of heme proteins in diseases characterized by myolysis and hemolysis.27 Moreover, a single clinical case report has just appeared describing the deficiency of HO-1 in an infant; although this clinical observation demonstrates susceptibility of cells derived from this patient to oxidative stress in vitro, the importance of degradation of heme per se in such toxicity was unresolved.36 Our data demonstrate that, in settings in which the absence of HO-1 renders organs such as the kidney exquisitely sensitive to heme proteins, marked elevations in tissue heme content occur.
Our studies, uncovering as they do, the toxicity of heme in the kidney and other organs, underscores the duality of heme: heme, linked as a prosthetic group to a number of proteins, provides diverse and indispensable cellular functions; and yet, in inordinate amounts, free heme is markedly injurious to tissues. Such a mechanism of tissue injury may be relevant to the recently recognized sensitivity of HO-1 -/- mice to endotoxin;37 endotoxin is known to destabilize heme proteins and increase cellular heme content:38 in such circumstances, the absence of HO-1 would render tissues particularly sensitive to the effects of endotoxin.
Previous studies demonstrate that the induction of HO-1 in states of heme protein-mediated injury is accompanied by increased ferritin synthesis;18,29 such increased amounts of ferritin, through the iron-binding and possibly other effects of this protein, may represent an added protectant against heme protein-mediated injury. Studies of ferritin synthesis in settings in which HO-1 is absent, as occurs in the HO-1 -/- mouse, would be of interest. This HO-1 -/- mouse model also provides an opportunity to test whether the deficiency of HO-1 renders tissues sensitive to the chronic inflammatory effects of heme proteins; additionally, it is of interest whether the deficiency of HO-1 renders tissues sensitive to oxidant and other forms of acute injury that are not overtly dependent on heme proteins.
Finally, the present studies contribute to the steadily accruing inventory on phenotypic patterns observed in knockout mice exhibiting the deletions of specific genes.39 Interestingly, an increasing number of knockout models are described in which the anticipated phenotype is not observed, an occurrence that perhaps reflects an underlying redundancy such that the loss of a given gene may be compensated for by the recruitment of other genes. Additionally, phenotypic changes may be observed that are not anticipated from such genetic deletion or may be at odds with the presumed functional role of a given gene. Neither of these considerations—redundancy that denies the appearance of a predicted phenotype nor perplexity in accounting for the observed phenotype—pertains to the present findings in this knockout model: the genetic deletion of HO-1 renders tissue exquisitely vulnerable to the damaging effects of heme proteins, thereby attesting to the indispensability of HO-1 in protecting tissues so exposed, and the failure of other remaining antioxidant systems to compensate for the loss of HO-1 in this inimical circumstance.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health grants DK-47060 and HL-55552 (to K. A. N.) and DK-43135 (to J. A.).
Accepted for publication January 28, 2000.
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