American Journal of Kidney Diseases
Volume 51, Issue 4 , Pages 678-690, April 2008

Heme Oxygenase 1: Does It Have a Role in Renal Cytoprotection?

  • Aisling E. Courtney, MPhil, MRCP

      Affiliations

    • Corresponding Author InformationAddress correspondence to Aisling E. Courtney, MPhil, MRCP, Regional Nephrology Unit, Belfast City Hospital-Level 11, Lisburn Rd, Belfast BT9 7AB, UK.
    • ,
  • A. Peter Maxwell, PhD, FRCP

Nephrology Research Group, Queen’s University of Belfast, Belfast City Hospital, Belfast BT9 7AB, UK.

Received 15 June 2007; accepted 28 November 2007. published online 07 March 2008.

Article Outline

Heme oxygenase (HO) was first identified as the rate-limiting enzyme in the degradative pathway of heme, but is now recognized to be involved in diverse biological processes. Different isoforms of HO exist; HO-1 (HMOX1) is ubiquitously present in mammalian tissue with low constitutive expression under physiological conditions, but is upregulated in response to a variety of potentially noxious stimuli. HO-1, an integral component of an important cytoprotective mechanism, mediates its action through removal of heme, the generation of heme breakdown reaction products (biliverdin, free iron, and carbon monoxide), and modulation of key cellular molecules. Data from experimental models in which HO-1 was induced or inhibited, together with observations in genetically modified animals, showed a beneficial effect of HO-1 in several pathways leading to kidney injury. The discovery of a functional guanosine thymine tandem repeat polymorphism in the promoter region of the human HO-1 gene has stimulated clinical investigations in a variety of diseases. However, despite theoretical and experimental support for an important pathophysiological role for HO-1, the relevance of this polymorphism in native kidney or renal transplant function is equivocal. This article reviews the molecular genetics of HO-1, its myriad cytoprotective effects allied to how these are mediated, and relates these findings to experimental and clinical evidence of HO-1 involvement in renal disease.

Index Words: Heme oxygenase, genetic polymorphism, renal injury

 

Cytoprotective mechanisms are crucial for the defense of cells, tissues, and organs against noxious external and internal stressors. Heme oxygenase 1 (HO-1 or HMOX1) is now recognized to be a key player in endogenous cytoprotection.1 Studies of the role of HO-1 in a variety of diseases have been stimulated further by the finding of a functionally significant polymorphism in the promoter of the HO-1 gene.2 The pathophysiological relevance of HO-1 and its regulation in renal disease increasingly is being elucidated.

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Case Vignette 

A 45-year-old man with hemodialysis-dependent end-stage renal disease secondary to immunoglobulin A nephropathy received a 3-HLA–mismatched deceased donor kidney transplant. The donor, a 65-year-old man, had experienced anoxic brain injury during cardiac arrest. Serum creatinine level at the time of organ retrieval was 2.1 mg/dL (186 μmol/L). Cold ischemic time before transplantation surgery was 25 hours, and intraoperative warm ischemic time was 56 minutes. Although the kidney allograft was described by the transplant surgeon as “well perfused” at the end of surgery, the recipient remained oliguric postoperatively despite appropriate fluid replacement. He remained hemodynamically stable, but had delayed graft function with continued dialysis dependence for 9 days postoperatively. A transplant renal biopsy on day 7 after engraftment showed widespread acute tubular injury without evidence of rejection.

This common scenario of delayed renal graft function is a risk factor for subsequent acute transplant rejection and also may adversely affect long-term graft survival. Ischemia-reperfusion (IR) injury in the allograft is compounded by hemodynamic instability in the donor before organ retrieval and prolonged cold and warm ischemic times. A complex interplay of cytotoxic and cytoprotective pathways influence the clinical course of this IR injury in renal transplant recipients, and there is increasing interest in endogenous cytoprotective molecules that may alter the response to injury. Emerging evidence suggests a role for the enzyme HO-1 in regulating the severity of tissue injury in this setting.

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Pathogenesis 

Function of HO 

HO was first recognized as catalyzing the rate-limiting step in the principal degradative mechanism of heme (iron protoporphyrin IX).3 The heme ring is cleaved in a reaction requiring oxygen and nicotinamide adenine dinucleotide phosphate (NADP) and converted to biliverdin, with the concomitant release of iron and emission of carbon monoxide (CO) in equimolar quantities. Biliverdin is then reduced to bilirubin by biliverdin reductase (Fig 1).

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  • Figure 1. 

    Heme oxygenase–catalyzed degradation of heme. Abbreviations: NADPH, reduced form of NADP; NADP, nicotinamide adenine dinucleotide phosphate; Fe, iron; CO, carbon monoxide.

Two distinct isoforms of HO, the products of different genes, have been identified.4 HO-1 is found intracellularly in microsomes and is regulated transcriptionally. It is ubiquitously present in mammalian tissue, although HO-1 expression is relatively low under physiological conditions, except in the spleen, where the action of HO-1 is critical to recycling of iron from senescent erythrocytes. HO-2 shares 40% amino acid homology with HO-1 and is constitutively expressed in a more limited distribution. It is localized to mitochondria and probably regulates a variety of cellular functions. A third distinct isoform of HO (HO-3) was postulated, but the evidence is now clear that this is a pseudogene.5

The human HO-1 gene is located on chromosome 22q12 and is approximately 14 kb long with 5 exons.6 Control of HO-1 gene transcription is complex and tightly regulated, with both species and tissue specificity.1 A wide variety of stimuli were shown to induce HO-1, including heme, heavy metals, hydrogen peroxide, oxidized low-density lipoprotein, hypoxia, endotoxin, nitric oxide and nitric oxide donors, cytokines, growth factors, angiotensin II, shear stress, and UV radiation.1, 7 A significant shift in cellular redox is a feature common to many of these stimuli. Multiple regulatory elements control human HO-1 gene transcription. These include numerous transcription factor consensus binding sites in both the proximal and distal 5′ promoter sequence and an internal enhancer region.1, 8, 9 Multiple copies of stress-response elements and a cadmium-response element upregulate HO-1 gene expression in concert with other important transcription factors, including Jun B, activator proteins 1 and 2, and nuclear factor-κB (NF-κB). The transcription factors Bach1 and Jun D act as negative regulators of human HO-1 gene expression. Additionally, a functional polymorphic dinucleotide guanosine thymine (GT) repeat region is present in the proximal promoter region (approximately encompassing the region from nucleotide −258 to nucleotide −198, where +1 is the transcription start site). Figure 2 is a limited schematic representation of the major regulatory elements of the human HO-1 gene.

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  • Figure 2. 

    Schematic representation of human heme oxygenase-1 gene. The regulatory sequence shown is limited to components of the proximal promoter region. Abbreviations: HSE, heat shock element; (GT)n, polymorphic GT repeat sequence; NF-κB, nuclear factor-κB; AP-2, activator protein-2; StRE, stress-responsive element; CdRE, cadmium-response element. The TATA box at the transcription start site is also shown. A more complete illustration of the known transcriptions factors influencing HO-1 expression is available in Sikorski et al1 and Alam and Cook.8

The reported number of GT repeats ranges from 12 to 40, although there is a bimodal distribution in most populations, with the main alleles being 23 and 30 repeats.2 HO-1 messenger RNA (mRNA) expression and enzyme activity are greater when the GT repeat length is short, rather than long. No protein has been identified that binds to this region, and it is postulated that a conformational change accounts for the modulation of transcriptional activity.2 A left-handed double helix structure (Z-DNA conformation) may be formed by the alternating purine-pyrimidine sequence, an arrangement that has diminished transcriptional activity in other genes.10, 11

Results of transient transfection assays using luciferase promoter constructs were consistent with an in vitro assay using lymphoblastoid cell lines with known HO-1 GT repeat lengths.12, 13, 14 Cells homozygous for short (GT)n length had significantly greater HO-1 expression and resistance to oxidant-induced apoptosis than long (GT)n length homozygotes, demonstrating that the (GT)n length polymorphism was functionally significant.

One important caveat in interpreting the literature is that significant interspecies differences are recognized in the transcriptional regulation of HO-1 expression. Examples include the absence of a (GT)n region in the mouse gene1 and nonfunction of the heat shock response element in the human gene in contrast to the rat HO-1, which functions as a heat shock protein and is known as HSP32.15 Furthermore, hypoxia induces HO-1 expression in multiple rodent, bovine, and monkey cell lines, but, interestingly, represses the human HO-1 gene in a variety of human cells.16, 17, 18, 19, 20, 21 The direct translation of HO-1 research findings from “bench to bedside” must be qualified by appreciating that HO-1 gene expression in response to certain stimuli may be different in humans compared with the studied rodent models.

The robustness of the response of the HO-1 gene to such a variety of stimuli reflects the wide-ranging biological implications of HO-1 generation, extending far beyond its initial identified role as the rate-limiting step in heme degradation. However, the tight regulation of HO-1 gene transcription and absence of a higher constitutive expression reflect the potential of this “protective” gene to induce injury under certain circumstances.7 Each reaction product can be harmful and, in sufficient quantities, perpetrate tissue injury with resulting enhanced susceptibility to oxidative stress.22 Thus, HO-1 is not exclusively cytoprotective or cytotoxic, but is involved in a complex equilibrium of inflammatory and reparative cellular processes.

Protective Effects of HO-1 

The cytoprotective qualities of HO-1 induction were first shown in 1992 when prior exposure of a rat kidney to small quantities of hemoglobin upregulated HO-1 expression and provided dramatic protection from tissue injury after subsequent exposure to larger quantities of hemoglobin or myoglobin.23 Conversely, the presence of an HO-1 inhibitor exacerbated renal injury.

The protection afforded by HO-1 generation probably reflects a combination of factors. The postulated mechanisms are the removal of the reaction substrate (heme), biological effects of the reaction products (CO, biliverdin, bilirubin, and free iron inducing ferritin production), a suppressive effect on monocyte chemoattractant protein 1 (MCP-1), and modulation of cell-cycle regulators.4, 24, 25, 26

CO at low concentrations behaves as a regulatory molecule in many cellular and biological processes and may mediate many of the effects of HO-1.27, 28, 29, 30, 31, 32, 33, 34 CO acts through a variety of pathways, including increasing cyclic guanosine monophosphate through activation of guanylate cyclase (cGMP),27, 28 modulation of inducible nitric oxide synthase (iNOS),29 regulation of protein kinases,27, 30, 31, 32 an effect on vascular smooth muscle cells,33, 35 and moderating the activity of key cell-cycle regulators.27, 34 Physiological consequences of CO are complex and can differ depending on the tissue involved. A full discussion is beyond the remit of this article.

Consequences of HO-1 production can be categorized as antioxidant, anti-inflammatory, antiproliferative, antiapoptotic, immunomodulatory, and vasorelaxant (Table 1).

Table 1. Cytoprotective Effects of Heme Oxygenase 1 and How They Are Mediated
Heme Degradation Reaction MediatedOther Effects
HemeCarbon MonoxideBiliverdin, BilirubinIron With Co-induction of FerritinMCP-1 SuppressionCell-Cycle Regulators
AntioxidantYes24—Yes36Yes37Yes25, 44—
Anti-inflammatoryYes?40Yes30, 41Yes36, 42—Yes25, 44—
Antiproliferative—Yes27, 33————
Antiapoptotic—Yes32, 28—Yes32—Yes26, 45
Immunomodulatory—Yes31, 34————
Vasorelaxant—Yes35Yes48———

Abbreviation: MCP-1, monocyte chemoattractant protein 1.

Antioxidant Effect 

The antioxidant effect of HO-1 is mediated by at least 4 pathways: removal of pro-oxidant heme by degradation24; generation of biliverdin and bilirubin, which are both potent scavengers of peroxyl radicals36; coinduction of ferritin to sequester free iron and reduce the generation of hydroxyl radicals37; and suppression of the pro-oxidant MCP-1.25

Anti-inflammatory Effect 

Induction of HO-1 resulted in marked suppression of acute inflammation in a rat model,38 and an increased inflammatory state was reported in a case of human HO-1 deficiency.39 Anti-inflammatory effects of HO-1 may be mediated by the removal of heme, production of CO and biliverdin, and inhibition of MCP-1.

Heme is a key constituent of a number of proinflammatory enzymes, such as inducible nitric oxide synthase, cyclo-oxygenase, and cytochrome p450 mono-oxygenases.40 Theoretically, removal of heme by HO-1 activation may limit the synthesis or optimal activity of such enzymes and impair the inflammatory response.

CO induces p38 mitogen activated protein (MAP) kinase, which suppresses the proinflammatory phenotype of monocytes/macrophages.30 There is decreased production of the proinflammatory cytokines tumor necrosis factor α, interleukin 1β, and macrophage inflammatory protein 1β and increased production of interleukin 10, which has anti-inflammatory properties. Inhibition of p38 MAP kinase abrogated the protective effect of HO-1 induction in human proximal tubular epithelial cell lines.41

Biliverdin inhibits the C1 step of the classical complement pathway in vitro and in vivo and prevents complement-associated anaphylactic reactions.36 Inhibition of the expression of P-selectin and E-selectin on vascular endothelial cells by HO-1 impairs the inflammatory response and may be mediated by biliverdin.42

MCP-1 is involved in tissue injury in a variety of conditions, including acute inflammatory states.43 It is a very potent chemoattractant for monocytes, recruits memory T cells and natural killer cells, activates the endothelium, is procoagulant, facilitates smooth muscle cell proliferation, and activates a proinflammatory cascade. In HO-1 knockout mice, there was a 5-fold greater baseline level of MCP-1 and enhanced expression of MCP-1 in response to stress.25, 44 Regulation of MCP-1 may be under the tonic suppressive effect of HO-1.

Antiproliferative Effect 

The antiproliferative effect of HO-1 principally has been studied in vascular smooth muscle cells and appears to be mediated by CO. This effect may be through the activation of cGMP and p38 MAP kinase27 and by autocrine regulation of specific components of the cell-cycle machinery to limit vascular smooth muscle cell proliferation.33

Antiapoptotic Effect 

Suppression of apoptosis may be mediated through CO production,28, 32 iron chelation,32 and modulation of such key cell-cycle regulators as the cyclin-dependent kinase inhibitor p21 with growth arrest at the G0/G1 phase of the cell cycle.26, 45

Immunomodulatory Effect 

Overexpression of HO-1 was first shown to affect cell-mediated immune effector functions in 1998, with marked suppression of T-cell–mediated and natural killer cell–mediated cytotoxicity.15 CO inhibits extracellular-signal–regulated kinase phosphorylation in activated T cells, suppressing interleukin-2 production and T-cell proliferation,31 but also may be influential through the inhibition of caspase 3 and caspase 8.34 There now is evidence suggesting HO-1 is intrinsically involved in the regulation of CD4+ T cells.46 Additionally, HO-1 was reported to inhibit the maturation and proinflammatory function of dendritic cells, which have an important role in transplant immunobiology.47

Vasorelaxant Effect 

The vasorelaxant effect of HO-1 probably is mediated by CO35 and bile pigments.48 Interactions with nitric oxide and superoxide anions are complex and not completely delineated.

Hence, the influence of HO-1 extends far beyond the degradative pathway for heme in which it was first recognized. Experimental models and clinical studies of HO-1 (GT)n length polymorphism in diverse conditions have been reported and reviewed elsewhere.2

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Recent Advances 

Experimental Models of HO-1 in Renal Disease 

HO has been implicated in both heme-dependent and heme-independent experimental models of renal injury.

Heme-Mediated Injury 

Renal tubular cells may be exposed to excess heme protein overtly or covertly. Overt exposure occurs with the disproportionate release of heme proteins from myocytes or erythrocytes, as in rhabdomyolysis, paroxysmal nocturnal hemoglobinuria, and the hematuric nephritides. Endocytosis and subsequent phagocytosis in the lysosomal system lead to an increase in intracellular heme that may be tubulotoxic.49, 50 The intramuscular injection of hypertonic glycerol induces myolysis and hemolysis and was used widely as a model of heme protein injury. In 1992, Nath et al23 first showed the cytoprotective properties of HO-1 in this model. Confirmation of the critical role of HO-1 was provided by the uniformly fatal outcome of hypertonic glycerol–mediated injury in knockout mice (HO-1−/−) with fulminant irreversible renal failure, whereas in wild-type (HO-1+/+) mice, there was rapid induction of HO-1 and mild reversible renal dysfunction without mortality.51

Heme proteins are abundant in intracellular organelles and may be released during periods of oxidative stress that destabilize the intracellular environment. A rapid increase in microsomal heme concentration can occur with endotoxin and ischemic exposure.52, 53 Mitochondria and nuclei are most susceptible to the noxious effects of intracellular heme, with marked structural injury evident within 3 hours of the insult. In clinical practice, IR injury is the common pathway mediating renal damage from many insults,54 and there is robust upregulation of HO-1 in IR injury. The induction of HO-1 before IR decreases the rise in microsomal heme and ameliorates renal injury.55, 56 Administration of the HO-1 inhibitor tin protoporphyrin negates this benefit.53, 56 There is evidence that the beneficial effects of HO-1 upregulation are mediated at least in part by CO57 and biliverdin.58 The latter study concluded that CO and biliverdin had synergistic effects in decreasing the upregulation of proinflammatory molecules, decreasing lipid peroxidation, and improving blood flow in Lewis rat cardiac and renal transplant models.

Non–Heme-Mediated Injury 

In addition to the release of intracellular heme inducing HO-1 generation, oxidative stress in IR injury activates the redox-sensitive transcription factor NF-κB,59 for which there is a binding site on the HO-1 gene promoter. NF-κB also upregulates the expression of MCP-1, which facilitates infiltration of monocytes/macrophages into the renal interstitium. There is a marked decrease in interstitial inflammatory infiltrate and protection from acute tubular necrosis in the absence of effective MCP-1.60, 61, 62 In HO-1 knockout mice, there is upregulation of NF-κB and MCP-1 in both stressed and unstressed situations. An ischemic insult, innocuous in wild-type animals, resulted in marked tubular injury and was fatal in the majority of null animals.44 In wild-type animals, there was upregulation of HO-1, and the marked increase in NF-κB and MCP-1 levels seen in null mice was absent.

In inflamed glomeruli, in a model of anti–glomerular basement membrane nephritis, HO-1 was detected in invading macrophages, but also was expressed by mesangial cells in response to nitric oxide.63, 64 Acute glomerular injury, precipitated by nephrotoxic serum, may confer resistance to subsequent tubular injury through HO-1 induction.65

Oxidative stress was implicated in the progression of inherited and acquired polycystic kidney disease, and 1 study showed that HO-1 mRNA increased in proportion to disease severity.66

In a unilateral ureteric obstruction model, there was significant upregulation of HO-1 mRNA in the interstitium within 12 hours of the initiating insult, with HO-1 protein activity peaking at 2 days.67 It is possible that the hypoxia resulting from diminished renal plasma flow leads to oxidative stress in the interstitium and upregulation of HO-1, with initiation of a cascade of inflammatory molecules and profibrotic cytokines.68

Angiotensin II is implicated in progressive renal injury and cardiovascular disease. Its effects are mediated through hemodynamic and nonhemodynamic actions.69 The latter includes elaboration of inflammatory molecules, fibrogenic cytokines, various growth factors, and induction of oxidative stress. Angiotensin II can induce HO-1 expression in proximal tubular epithelial cells70 and increase expression of NF-κB and MCP-1.71 MCP-1 stimulates transforming growth factor β (TGF-β) expression,72 stimulating extracellular matrix formation. However, TGF-β can inhibit MCP-1 in a feedback loop and, in addition, induce de novo HO-1 synthesis73 in human proximal tubular cell lines. Thus, HO-1 may modulate the inflammatory response and protect against excess TGF-β activity.

Clinical Studies of HO-1 in Renal Disease 

HO-1 Deficiency 

The importance of HO-1 in renal pathophysiology is evident from the description by Ohta et al74 of the clinical and histopathologic course of a boy with HO-1 deficiency. Hematuria and proteinuria were detected, and although renal clearance remained within the normal range, histological examination showed progressive tubulointerstitial injury with tubular dilatation or atrophy, inflammatory cell infiltrate, and interstitial fibrosis. Glomerular changes on light microscopy were relatively mild. Electron microscopy showed widespread detachment of the endothelium and subendothelial deposits.

Sophisticated mechanisms must exist to protect tubular epithelial cells from the potential damage resulting from exposure to high concentrations of filtered substances, and HO-1 induction is probably one such mechanism. In this case, the tubuloprotective mechanisms were overwhelmed and resulted in marked tubulointerstitial injury.74

Histological Analysis of HO-1 Expression 

The same group examined HO-1 expression in a series of 74 patients with varying renal diagnoses.75 HO-1 was detected in all biopsy specimens regardless of the primary renal diagnosis and was localized to tubular epithelial cells. Intensity of HO-1 staining correlated with proteinuria and degree of hematuria.

(GT)n Polymorphism 

No association was found between the functional HO-1 (GT)n promoter polymorphism and progression to end-stage renal disease in patients with either immunoglobulin A glomerulonephritis or polycystic kidney disease.76

HO-1 in Renal Transplantation 

Prolongation of graft survival requires minimization of immune and nonimmune insults, particularly in the peritransplantation period.77 IR triggers the injury response, with oxidative stress having an important role in activation of the endothelium and leukocytes.78, 79, 80 An acute inflammatory response then perpetuates the injury and upregulates the immune system through the infiltration of lymphocytes, increased expression of major histocompatibility complex molecules, and recruitment of such antigen-presenting cells as dendritic cells to the graft.81, 82, 83, 84 Immune damage causes further injury and augments the influx of inflammatory molecules, with increased fibrogenesis and epithelial-to-mesenchymal transition that may be provoked by T-cell–associated TGF-β or oxidative stress.85, 86 Apoptosis is a prominent response to injury in this setting.87

Thus, the multiple pathways leading to transplant injury potentially could be modified positively by increased HO-1 expression, and this is supported by experimental evidence.

Experimental Models 

Animal models of renal transplantation showed protective effects of HO-1 expression in attenuation of IR injury, immunomodulation, and minimization of chronic damage.88, 89, 90, 91, 92, 93 There is evidence that at least some of these effects are secondary to the production of CO and/or biliverdin.57, 58, 94 Peritransplantation induction of HO-1 in the recipient rather than the donor may be efficacious.95

The importance of both local and systemic induction of HO-1 was shown in cardiac transplant models.96, 97, 98, 99, 100, 101, 102 HO-1 expression also was reported as beneficial in hepatic,103, 104, 105 small-bowel,106 lung,107, 108 and islet-cell transplantation.109 Nevertheless, the beneficial outcomes in these experimental models cannot be attributed definitely to HO-1 because other cytoprotective mechanisms may have greater influence in these settings.

Histological Analysis 

In retrieval biopsy specimens, HO-1 mRNA levels were significantly greater in deceased donor kidney grafts compared with living donor grafts,110 with an associated increase in MCP-1 and TGF-β expression. However, there were positive correlations with graft function at 1 and 3 years after transplantation in only the living donor group.

Conversely, a different group reported that in intraoperative renal allograft biopsy specimens, HO-1 levels were consistently lower in the deceased than living donor organs.111 In a separate study, increased intraoperative HO-1 expression was predictive of acute rejection,112 but there was no independent association with graft function after 6 months.

In allograft biopsy specimens from patients with increasing serum creatinine values, increased HO-1 gene expression was associated with acute rejection, but not with other pathological findings.113

In failed explanted allografts, HO-1 expression was on average 3-fold less than in non–transplant nephrectomy specimens.114 However, HO-1 expression was widespread in glomeruli, proximal and distal tubules, interstitium, and vessels in allografts in contrast to the limited proximal tubular distribution in control kidneys. The clinical relevance of these findings is uncertain. It appeared there was specific upregulation of HO-1 in certain compartments within an injured graft, but overall expression was less than basal constitutive levels.

Thus, despite the strong experimental evidence suggesting that increased HO-1 expression protects against graft injury, histological data from clinical studies were conflicting. This may reflect in part the differences in populations, times, and HO-1 analysis between centers.

(GT)n Polymorphism 

Initial studies that examined the functional relevance of the HO-1 promoter (GT)n tandem repeat polymorphism in a clinical setting of renal transplantation reported that grafts from short-homozygote and heterozygote donors had significantly lower 1-year creatinine levels and improved 5-year graft survival rates compared with grafts from long-homozygote donors.115, 116 However, a subsequent study with greater power and prolonged follow-up found no evidence of a protective effect for the short allele of the HO-1 gene promoter polymorphism in donor or recipient on graft or recipient survival.117

Similarly, despite encouraging data from animal models, there was no association between the HO-1 genotype and cardiac transplantation outcomes in the clinical setting.118, 119

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Summary 

There is increasing experimental evidence of an important cytoprotective role for HO-1 in diverse organ systems. HO-1 induction limits cell injury in vitro and reduces kidney failure in experimental animal models. The pathway from kidney injury to beneficial renal cytoprotection from HO-1 reaction products is shown in Fig 3. Species differences in transcriptional regulation of HO-1 gene expression are important to bear in mind in extrapolating such findings to clinical practice.

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  • Figure 3. 

    Induction of heme oxygenase 1 (HO-1) gene expression by multiple mediators of renal injury leading to potential renal cytoprotection. Abbreviation: NF-κB, nuclear factor-κB.

HO-1 gene promoter polymorphism studies in clinical transplantation settings yielded contrasting results, and despite theoretical and experimental support for a role of HO-1 as an important antiatherogenic molecule, in clinical studies, benefit was shown in only a limited number of patients with atheromatous disease.13, 120, 121 It is essential that results from a single population, such as the finding that the short allele was protective against arteriovenous fistula failure in Chinese hemodialysis patients,122 are replicated in independent studies.

There are generic limitations associated with animal models and analysis of a single gene or molecule. Pharmacological induction of HO-1 before injury was used in many models, and this temporal difference in HO-1 expression may be important. Use of transgenic animals can surmount the potential pitfalls of pharmacological manipulation; however, the degree of HO-1 production may greatly exceed the physiological HO-1 concentration achieved with even a short number of GT repeats. There are specific disadvantages in transplant models in which the caliber of donors and recipients and prescription of immunomodulatory medications rarely reflect clinical practice.

Genetic association studies are difficult to replicate, particularly in multifactorial disorders.123 Redundancy within the milieu of protective gene variants or molecules in renal disease probably allows compensation for a genetic predisposition toward lower HO-1 production. It is possible that there may be a beneficial effect from the (GT)n tandem repeat polymorphism that is masked by the effect of other gene polymorphisms.

This does not exclude the possibility that augmentation of the HO-1 response potentially would be beneficial. Use of dopamine in brain-dead donors is reported to be beneficial in renal transplantation, with evidence that dopamine can cause upregulation of HO-1.124, 125 Curcumin also can induce HO-1, and in a randomized control trial, oral administration to the recipient after transplantation improved graft outcomes.126, 127 Insulin was shown to induce HO-1 in vitro, but has not yet been applied in a clinical setting.128 Likewise, a decrease in oxidative damage related to dialysis membrane activation by the preinduction of HO-1 has yet to be translated from the experimental environment.129

In conclusion, there are robust experimental data to suggest that the role of HO-1 extends far beyond degradation of heme and that it is an important cytoprotective molecule in numerous pathophysiological processes. The antioxidant, anti-inflammatory, antiproliferative, antiapoptotic, and immunomodulatory effects of HO-1 are mediated through the biological activity of the reaction products, removal of the substrate heme, an effect on such molecules as MCP-1, and key cell-cycle regulators. Clinical studies considering the functional (GT)n tandem repeat polymorphism in the HO-1 gene promoter were equivocal, with a protective effect of the short allele in some reports only. Additional work is required to determine whether induction of HO-1 will be of benefit in minimizing renal injury in native and transplanted kidneys.

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Acknowledgements 

Support: Dr Courtney receives support from the Northern Ireland Kidney Research Fund.

Financial Disclosure: None.

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References 

  1. Sikorski EM, Hock T, Hill-Kapturczak N, Agarwal A. The story so far: Molecular regulation of the heme oxygenase-1 gene in renal injury. Am J Physiol Renal Physiol. 2004;286:F425–F441
  2. Exner M, Minar E, Wagner O, Schillinger M. The role of heme oxygenase-1 promoter polymorphisms in human disease. Free Radic Biol Med. 2004;37:1097–1104
  3. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A. 1968;61:748–755
  4. Maines MD. The heme oxygenase system: A regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997;37:517–554
  5. Hayashi S, Omata Y, Sakamoto H, et al. Characterization of rat heme oxygenase-3 gene (Implication of processed pseudogenes derived from heme oxygenase-2 gene). Gene. 2004;336:241–250
  6. Kutty RK, Kutty G, Rodriguez IR, Chader GJ, Wiggert B. Chromosomal localization of the human heme oxygenase genes: Heme oxygenase-1 (HMOX1) maps to chromosome 22q12 and heme oxygenase-2 (HMOX2) maps to chromosome 16p13.3. Genomics. 1994;20:513–516
  7. Platt JL, Nath KA. Heme oxygenase: Protective gene or Trojan horse. Nat Med. 1998;4:1364–1365
  8. Alam J, Cook JL. How many transcription factors does it take to turn on the heme oxygenase-1 gene?. Am J Respir Cell Mol Biol. 2007;36:166–174
  9. Hock TD, Liby K, Wright MM, et al. JunB and JunD regulate human heme oxygenase-1 gene expression in renal epithelial cells. J Biol Chem. 2007;282:6875–6886
  10. Rich A, Nordheim A, Wang AH. The chemistry and biology of left-handed Z-DNA. Annu Rev Biochem. 1984;53:791–846
  11. Naylor LH, Clark EM. d(TG)n.d(CA)n sequences upstream of the rat prolactin gene form Z-DNA and inhibit gene transcription. Nucleic Acids Res. 1990;18:1595–1601
  12. Yamada N, Yamaya M, Okinaga S, et al. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. Am J Hum Genet. 2000;66:187–195
  13. Chen YH, Lin SJ, Lin MW, et al. Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Hum Genet. 2002;111:1–8
  14. Hirai H, Kubo H, Yamaya M, et al. Microsatellite polymorphism in heme oxygenase-1 gene promoter is associated with susceptibility to oxidant-induced apoptosis in lymphoblastoid cell lines. Blood. 2003;102:1619–1621
  15. Woo J, Iyer S, Cornejo MC, et al. Stress protein-induced immunosuppression: Inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32). Transpl Immunol. 1998;6:84–93
  16. Kitamuro T, Takahashi K, Ogawa K, et al. Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells. J Biol Chem. 2003;278:9125–9133
  17. Lee PJ, Jiang BH, Chin BY, et al. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem. 1997;272:5375–5381
  18. Motterlini R, Foresti R, Intaglietta M, Winslow RM. NO-mediated activation of heme oxygenase: Endogenous cytoprotection against oxidative stress to endothelium. Am J Physiol. 1996;270:H107–H114
  19. Takahashi S, Takahashi Y, Yoshimi T, Miura T. Oxygen tension regulates heme oxygenase-1 gene expression in mammalian cell lines. Cell Biochem Funct. 1998;16:183–193
  20. Yang ZZ, Zou AP. Transcriptional regulation of heme oxygenases by HIF-1alpha in renal medullary interstitial cells. Am J Physiol Renal Physiol. 2001;281:F900–F908
  21. Kacimi R, Chentoufi J, Honbo N, Long CS, Karliner JS. Hypoxia differentially regulates stress proteins in cultured cardiomyocytes: Role of the p38 stress-activated kinase signaling cascade, and relation to cytoprotection. Cardiovasc Res. 2000;46:139–150
  22. Maruhashi K, Kasahara Y, Ohta K, et al. Paradoxical enhancement of oxidative cell injury by overexpression of heme oxygenase-1 in an anchorage-dependent cell ECV304. J Cell Biochem. 2004;93:552–562
  23. Nath KA, Balla G, Vercellotti GM, et al. Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest. 1992;90:267–270
  24. Ryter SW, Tyrrell RM. The heme synthesis and degradation pathways: Role in oxidant sensitivity (Heme oxygenase has both pro- and antioxidant properties). Free Radic Biol Med. 2000;28:289–309
  25. Nath KA, Vercellotti GM, Grande JP, et al. Heme protein-induced chronic renal inflammation: Suppressive effect of induced heme oxygenase-1. Kidney Int. 2001;59:106–117
  26. Inguaggiato P, Gonzalez-Michaca L, Croatt AJ, Haggard JJ, Alam J, Nath KA. Cellular overexpression of heme oxygenase-1 up-regulates p21 and confers resistance to apoptosis. Kidney Int. 2001;60:2181–2191
  27. Otterbein LE, Zuckerbraun BS, Haga M, et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med. 2003;9:183–190
  28. Gunther L, Berberat PO, Haga M, et al. Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplantation. Diabetes. 2002;51:994–999
  29. Stevenson TH, Gutierrez AF, Alderton WK, Lian L, Scrutton NS. Kinetics of CO binding to the haem domain of murine inducible nitric oxide synthase: Differential effects of haem domain ligands. Biochem J. 2001;358:201–208
  30. Otterbein LE, Bach FH, Alam J, et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000;6:422–428
  31. Pae HO, Oh GS, Choi BM, et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol. 2004;172:4744–4751
  32. Brouard S, Otterbein LE, Anrather J, et al. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med. 2000;192:1015–1026
  33. Peyton KJ, Reyna SV, Chapman GB, et al. Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth. Blood. 2002;99:4443–4448
  34. Song R, Mahidhara RS, Zhou Z, et al. Carbon monoxide inhibits T lymphocyte proliferation via caspase-dependent pathway. J Immunol. 2004;172:1220–1226
  35. Thorup C, Jones CL, Gross SS, Moore LC, Goligorsky MS. Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS. Am J Physiol. 1999;277:F882–F889
  36. Nakagami T, Toyomura K, Kinoshita T, Morisawa S. A beneficial role of bile pigments as an endogenous tissue protector: Anti-complement effects of biliverdin and conjugated bilirubin. Biochim Biophys Acta. 1993;1158:189–193
  37. Juckett MB, Balla J, Balla G, Jessurun J, Jacob HS, Vercellotti GM. Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro. Am J Pathol. 1995;147:782–789
  38. Willis D, Moore AR, Frederick R, Willoughby DA. Heme oxygenase: A novel target for the modulation of the inflammatory response. Nat Med. 1996;2:87–90
  39. Yachie A, Niida Y, Wada T, et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999;103:129–135
  40. White KA, Marletta MA. Nitric oxide synthase is a cytochrome P-450 type hemoprotein. Biochemistry. 1992;31:6627–6631
  41. Lee HT, Xu H, Ota-Setlik A, Emala CW. Oxidant preconditioning protects human proximal tubular cells against lethal oxidant injury via p38 MAPK and heme oxygenase-1. Am J Nephrol. 2003;23:324–333
  42. Vachharajani TJ, Work J, Issekutz AC, Granger DN. Heme oxygenase modulates selectin expression in different regional vascular beds. Am J Physiol Heart Circ Physiol. 2000;278:H1613–H1617
  43. Daly C, Rollins BJ. Monocyte chemoattractant protein-1 (CCL2) in inflammatory disease and adaptive immunity: Therapeutic opportunities and controversies. Microcirculation. 2003;10:247–257
  44. Pittock ST, Norby SM, Grande JP, et al. MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates. Kidney Int. 2005;68:611–622
  45. Gonzalez-Michaca L, Farrugia G, Croatt AJ, Alam J, Nath KA. Heme: A determinant of life and death in renal tubular epithelial cells. Am J Physiol Renal Physiol. 2004;286:F370–F377
  46. McDaid J, Yamashita K, Chora A, et al. Heme oxygenase-1 modulates the allo-immune response by promoting activation-induced cell death of T cells. FASEB J. 2005;19:458–460
  47. Chauveau C, Remy S, Royer PJ, et al. Heme oxygenase-1 expression inhibits dendritic cell maturation and proinflammatory function but conserves IL-10 expression. Blood. 2005;106:1694–1702
  48. Kawamura K, Ishikawa K, Wada Y, et al. Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arterioscler Thromb Vasc Biol. 2005;25:155–160
  49. Nath KA, Grande JP, Croatt AJ, Likely S, Hebbel RP, Enright H. Intracellular targets in heme protein-induced renal injury. Kidney Int. 1998;53:100–111
  50. Bunn HF, Jandl JH. The renal handling of hemoglobin (II. Catabolism). J Exp Med. 1969;129:925–934
  51. Nath KA, Haggard JJ, Croatt AJ, Grande JP, Poss KD, Alam J. The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo. Am J Pathol. 2000;156:1527–1535
  52. Bissell DM, Hammaker LE. Cytochrome P-450 heme and the regulation of hepatic heme oxygenase activity. Arch Biochem Biophys. 1976;176:91–102
  53. Shimizu H, Takahashi T, Suzuki T, et al. Protective effect of heme oxygenase induction in ischemic acute renal failure. Crit Care Med. 2000;28:809–817
  54. Grace PA. Ischaemia-reperfusion injury. Br J Surg. 1994;81:637–647
  55. Yoneya R, Nagashima Y, Sakaki K, et al. Hemolysate pretreatment ameliorates ischemic acute renal injury in rats. Nephron. 2002;92:407–413
  56. Toda N, Takahashi T, Mizobuchi S, et al. Tin chloride pretreatment prevents renal injury in rats with ischemic acute renal failure. Crit Care Med. 2002;30:1512–1522
  57. Neto JS, Nakao A, Kimizuka K, et al. Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide. Am J Physiol Renal Physiol. 2004;287:F979–F989
  58. Nakao A, Neto JS, Kanno S, et al. Protection against ischemia/reperfusion injury in cardiac and renal transplantation with carbon monoxide, biliverdin and both. Am J Transplant. 2005;5:282–291
  59. Sung FL, Zhu TY, Au-Yeung KK, Siow YL, Karmin O. Enhanced MCP-1 expression during ischemia/reperfusion injury is mediated by oxidative stress and NF-kappaB. Kidney Int. 2002;62:1160–1170
  60. Cao CC, Ding XQ, Ou ZL, et al. In vivo transfection of NF-kappaB decoy oligodeoxynucleotides attenuate renal ischemia/reperfusion injury in rats. Kidney Int. 2004;65:834–845
  61. Furuichi K, Wada T, Iwata Y, et al. Gene therapy expressing amino-terminal truncated monocyte chemoattractant protein-1 prevents renal ischemia-reperfusion injury. J Am Soc Nephrol. 2003;14:1066–1071
  62. Furuichi K, Wada T, Iwata Y, et al. CCR2 signaling contributes to ischemia-reperfusion injury in kidney. J Am Soc Nephrol. 2003;14:2503–2515
  63. Mosley K, Wembridge DE, Cattell V, Cook HT. Heme oxygenase is induced in nephrotoxic nephritis and hemin, a stimulator of heme oxygenase synthesis, ameliorates disease. Kidney Int. 1998;53:672–678
  64. Datta PK, Lianos EA. Nitric oxide induces heme oxygenase-1 gene expression in mesangial cells. Kidney Int. 1999;55:1734–1739
  65. Vogt BA, Shanley TP, Croatt A, Alam J, Johnson KJ, Nath KA. Glomerular inflammation induces resistance to tubular injury in the rat (A novel form of acquired, heme oxygenase-dependent resistance to renal injury). J Clin Invest. 1996;98:2139–2145
  66. Maser RL, Vassmer D, Magenheimer BS, Calvet JP. Oxidant stress and reduced antioxidant enzyme protection in polycystic kidney disease. J Am Soc Nephrol. 2002;13:991–999
  67. Kawada N, Moriyama T, Ando A, et al. Increased oxidative stress in mouse kidneys with unilateral ureteral obstruction. Kidney Int. 1999;56:1004–1013
  68. Diamond JR, Kees-Folts D, Ding G, Frye JE, Restrepo NC. Macrophages, monocyte chemoattractant peptide-1, and TGF-beta 1 in experimental hydronephrosis. Am J Physiol. 1994;266:F926–F933
  69. Rosenberg ME, Smith LJ, Correa-Rotter R, Hostetter TH. The paradox of the renin-angiotensin system in chronic renal disease. Kidney Int. 1994;45:403–410
  70. Haugen EN, Croatt AJ, Nath KA. Angiotensin II induces renal oxidant stress in vivo and heme oxygenase-1 in vivo and in vitro. Kidney Int. 2000;58:144–152
  71. Ruiz-Ortega M, Bustos C, Hernandez-Presa MA, Lorenzo O, Plaza JJ, Egido J. Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis. J Immunol. 1998;161:430–439
  72. Wolf G, Jocks T, Zahner G, Panzer U, Stahl RA. Existence of a regulatory loop between MCP-1 and TGF-beta in glomerular immune injury. Am J Physiol Renal Physiol. 2002;283:F1075–F1084
  73. Hill-Kapturczak N, Truong L, Thamilselvan V, Visner GA, Nick HS, Agarwal A. Smad7-dependent regulation of heme oxygenase-1 by transforming growth factor-beta in human renal epithelial cells. J Biol Chem. 2000;275:40904–40909
  74. Ohta K, Yachie A, Fujimoto K, et al. Tubular injury as a cardinal pathologic feature in human heme oxygenase-1 deficiency. Am J Kidney Dis. 2000;35:863–870
  75. Morimoto K, Ohta K, Yachie A, et al. Cytoprotective role of heme oxygenase (HO)-1 in human kidney with various renal diseases. Kidney Int. 2001;60:1858–1866
  76. Courtney AE, McNamee PT, Heggarty S, Middleton D, Maxwell AP. Association of functional heme oxygenase-1 gene promoter polymorphism with polycystic kidney disease and IgA nephropathy. Nephrol Dial Transplant. 2008;23:608–611
  77. Shoskes DA, Cecka JM. Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection. Transplantation. 1998;66:1697–1701
  78. Daemen MA, de Vries B, Buurman WA. Apoptosis and inflammation in renal reperfusion injury. Transplantation. 2002;73:1693–1700
  79. Halloran PF, Homik J, Goes N, et al. The “injury response”: A concept linking nonspecific injury, acute rejection, and long-term transplant outcomes. Transplant Proc. 1997;29:79–81
  80. Laskowski I, Pratschke J, Wilhelm MJ, Gasser M, Tilney NL. Molecular and cellular events associated with ischemia/reperfusion injury. Ann Transplant. 2000;5:29–35
  81. Lu CY, Penfield JG, Kielar ML, Vazquez MA, Jeyarajah DR. Hypothesis: Is renal allograft rejection initiated by the response to injury sustained during the transplant process?. Kidney Int. 1999;55:2157–2168
  82. Goes N, Urmson J, Ramassar V, Halloran PF. Ischemic acute tubular necrosis induces an extensive local cytokine response (Evidence for induction of interferon-gamma, transforming growth factor-beta 1, granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-10). Transplantation. 1995;59:565–572
  83. Raftery MJ, Seron D, Koffman G, Hartley B, Janossy G, Cameron JS. The relevance of induced class II HLA antigens and macrophage infiltration in early renal allograft biopsies. Transplantation. 1989;48:238–243
  84. Austyn JM, Larsen CP. Migration patterns of dendritic leukocytes (Implications for transplantation). Transplantation. 1990;49:1–7
  85. Robertson H, Ali S, McDonnell BJ, Burt AD, Kirby JA. Chronic renal allograft dysfunction: The role of T cell-mediated tubular epithelial to mesenchymal cell transition. J Am Soc Nephrol. 2004;15:390–397
  86. Djamali A, Reese S, Yracheta J, Oberley T, Hullett D, Becker B. Epithelial-to-mesenchymal transition and oxidative stress in chronic allograft nephropathy. Am J Transplant. 2005;5:500–509
  87. Matsuno T, Sasaki H, Ishido N, et al. Apoptosis in human kidney allografts. Transplant Proc. 1996;28:1226–1227
  88. Wagner M, Cadetg P, Ruf R, Mazzucchelli L, Ferrari P, Redaelli CA. Heme oxygenase-1 attenuates ischemia/reperfusion-induced apoptosis and improves survival in rat renal allografts. Kidney Int. 2003;63:1564–1573
  89. Martins PN, Reuzel-Selke A, Jurisch A, et al. Induction of carbon monoxide in the donor reduces graft immunogenicity and chronic graft deterioration. Transplant Proc. 2005;37:379–381
  90. Tullius SG, Nieminen-Kelha M, Bachmann U, et al. Induction of heme-oxygenase-1 prevents ischemia/reperfusion injury and improves long-term graft outcome in rat renal allografts. Transplant Proc. 2001;33:1286–1287
  91. Tullius SG, Nieminen-Kelha M, Reutzel-Selke A, et al. Improvement of long-term function in renal allografts from ‘marginal donors’ following the induction of heme-oxygenase-1. Transplant Proc. 2001;33:1160–1161
  92. Blydt-Hansen TD, Katori M, Lassman C, et al. Gene transfer-induced local heme oxygenase-1 overexpression protects rat kidney transplants from ischemia/reperfusion injury. J Am Soc Nephrol. 2003;14:745–754
  93. Cuturi MC, Christoph F, Woo J, et al. RDP1258, a new rationally designed immunosuppressive peptide, prolongs allograft survival in rats: Analysis of its mechanism of action. Mol Med. 1999;5:820–832
  94. Neto JS, Nakao A, Toyokawa H, et al. Low-dose carbon monoxide inhalation prevents development of chronic allograft nephropathy. Am J Physiol Renal Physiol. 2006;290:F324–F334
  95. Bedard EL, Jiang J, Parry N, et al. Peritransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection. Transpl Int. 2005;18:341–349
  96. Sato K, Balla J, Otterbein L, et al. Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants. J Immunol. 2001;166:4185–4194
  97. Katori M, Buelow R, Ke B, et al. Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway. Transplantation. 2002;73:287–292
  98. Akamatsu Y, Haga M, Tyagi S, et al. Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. FASEB J. 2004;18:771–772
  99. Hancock WW, Buelow R, Sayegh MH, Turka LA. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes. Nat Med. 1998;4:1392–1396
  100. Tsui TY, Wu X, Lau CK, et al. Prevention of chronic deterioration of heart allograft by recombinant adeno-associated virus-mediated heme oxygenase-1 gene transfer. Circulation. 2003;107:2623–2629
  101. Braudeau C, Bouchet D, Tesson L, et al. Induction of long-term cardiac allograft survival by heme oxygenase-1 gene transfer. Gene Ther. 2004;11:701–710
  102. Araujo JA, Meng L, Tward AD, et al. Systemic rather than local heme oxygenase-1 overexpression improves cardiac allograft outcomes in a new transgenic mouse. J Immunol. 2003;171:1572–1580
  103. Kato H, Amersi F, Buelow R, et al. Heme oxygenase-1 overexpression protects rat livers from ischemia/reperfusion injury with extended cold preservation. Am J Transplant. 2001;1:121–128
  104. Amersi F, Buelow R, Kato H, et al. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest. 1999;104:1631–1639
  105. Wang XH, Wang K, Zhang F, et al. Heme oxygenase-1 alleviates ischemia/reperfusion injury in aged liver. World J Gastroenterol. 2005;11:690–694
  106. Squiers EC, Bruch D, Buelow R, Tice DG. Pretreatment of small bowel isograft donors with cobalt-protoporphyrin decreases preservation injury. Transplant Proc. 1999;31:585–586
  107. Song R, Kubo M, Morse D, et al. Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects. Am J Pathol. 2003;163:231–242
  108. Bonnell MR, Visner GA, Zander DS, et al. Heme-oxygenase-1 expression correlates with severity of acute cellular rejection in lung transplantation. J Am Coll Surg. 2004;198:945–952
  109. Pileggi A, Molano RD, Berney T, et al. Heme oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation. Diabetes. 2001;50:1983–1991
  110. Nijboer WN, Schuurs TA, van der Hoeven JA, et al. Effect of brain death on gene expression and tissue activation in human donor kidneys. Transplantation. 2004;78:978–986
  111. Lemos FB, Ijzermans JN, Zondervan PE, et al. Differential expression of heme oxygenase-1 and vascular endothelial growth factor in cadaveric and living donor kidneys after ischemia-reperfusion. J Am Soc Nephrol. 2003;14:3278–3287
  112. Avihingsanon Y, Ma N, Pavlakis M, et al. On the intraoperative molecular status of renal allografts after vascular reperfusion and clinical outcomes. J Am Soc Nephrol. 2005;16:1542–1548
  113. Avihingsanon Y, Ma N, Csizmadia E, et al. Expression of protective genes in human renal allografts: A regulatory response to injury associated with graft rejection. Transplantation. 2002;73:1079–1085
  114. Serinsoz E, Bock O, Kirsch T, et al. Compartment-specific quantitative gene expression analysis after laser microdissection from archival renal allograft biopsies. Clin Nephrol. 2005;63:193–201
  115. Exner M, Bohmig GA, Schillinger M, et al. Donor heme oxygenase-1 genotype is associated with renal allograft function. Transplantation. 2004;77:538–542
  116. Baan C, Peeters A, Lemos F, et al. Fundamental role for HO-1 in the self-protection of renal allografts. Am J Transplant. 2004;4:811–818
  117. Courtney AE, McNamee PT, Middleton D, Heggarty S, Patterson CC, Maxwell AP. Association of functional heme oxygenase-1 gene promoter polymorphism with renal transplantation outcomes. Am J Transplant. 2007;7:908–913
  118. Holweg CT, Balk AH, Uitterlinden AG, et al. Functional heme oxygenase-1 promoter polymorphism in relation to heart failure and cardiac transplantation. J Heart Lung Transplant. 2005;24:493–497
  119. Ullrich R, Exner M, Schillinger M, et al. Microsatellite polymorphism in the heme oxygenase-1 gene promoter and cardiac allograft vasculopathy. J Heart Lung Transplant. 2005;24:1600–1605
  120. Kaneda H, Ohno M, Taguchi J, et al. Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors. Arterioscler Thromb Vasc Biol. 2002;22:1680–1685
  121. Endler G, Exner M, Schillinger M, et al. A microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with increased bilirubin and HDL levels but not with coronary artery disease. Thromb Haemost. 2004;91:155–161
  122. Lin CC, Yang WC, Lin SJ, et al. Length polymorphism in heme oxygenase-1 is associated with arteriovenous fistula patency in hemodialysis patients. Kidney Int. 2006;69:165–172
  123. Colhoun HM, McKeigue PM, Davey Smith G. Problems of reporting genetic associations with complex outcomes. Lancet. 2003;361:865–872
  124. Schnuelle P, Yard BA, Braun C, et al. Impact of donor dopamine on immediate graft function after kidney transplantation. Am J Transplant. 2004;4:419–426
  125. van der Woude FJ, Schnuelle P, Yard BA. Preconditioning strategies to limit graft immunogenicity and cold ischemic organ injury. J Invest Med. 2004;52:323–329
  126. McNally SJ, Harrison EM, Ross JA, Garden OJ, Wigmore SJ. Curcumin induces heme oxygenase-1 in hepatocytes and is protective in simulated cold preservation and warm reperfusion injury. Transplantation. 2006;81:623–626
  127. Shoskes D, Lapierre C, Cruz-Correa M, et al. Beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation: A randomized placebo controlled trial. Transplantation. 2005;80:1556–1559
  128. Harrison EM, McNally SJ, Devey L, Garden OJ, Ross JA, Wigmore SJ. Insulin induces heme oxygenase-1 through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in renal cells. FEBS J. 2006;273:2345–2356
  129. Bhaskaran M, Radhakrishnan N, Patni H, Singh P, Chaudhary AN, Singhal PC. Dialysis membrane-induced oxidative stress: Role of heme oxygenase-1. Nephron Exp Nephrol. 2007;105:e24–e32

 Originally published online as doi:10.1053/j.ajkd.2007.11.033 on March 3, 2008.

PII: S0272-6386(08)00050-4

doi:10.1053/j.ajkd.2007.11.033

American Journal of Kidney Diseases
Volume 51, Issue 4 , Pages 678-690, April 2008

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