Volume 51, Issue 4, Pages 678-690 (April 2008)

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

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

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

Article Outline

• Abstract

• Case Vignette

• Pathogenesis

• Function of HO

• Protective Effects of HO-1

• Antioxidant Effect

• Anti-inflammatory Effect

• Antiproliferative Effect

• Antiapoptotic Effect

• Immunomodulatory Effect

• Vasorelaxant Effect

• Recent Advances

• Experimental Models of HO-1 in Renal Disease

• Heme-Mediated Injury

• Non–Heme-Mediated Injury

• Clinical Studies of HO-1 in Renal Disease

• HO-1 Deficiency

• Histological Analysis of HO-1 Expression

• (GT) Polymorphism

• HO-1 in Renal Transplantation

• Experimental Models

• Histological Analysis

• (GT) Polymorphism

• Summary

• Acknowledgment

• References

• Copyright

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.

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.

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 Mediated				Other Effects
	Heme	Carbon Monoxide	Biliverdin, Bilirubin	Iron With Co-induction of Ferritin	MCP-1 Suppression	Cell-Cycle Regulators
Antioxidant	Yes24	—	Yes36	Yes37	Yes25, 44	—
Anti-inflammatory	Yes?40	Yes30, 41	Yes36, 42	—	Yes25, 44	—
Antiproliferative	—	Yes27, 33	—	—	—	—
Antiapoptotic	—	Yes32, 28	—	Yes32	—	Yes26, 45
Immunomodulatory	—	Yes31, 34	—	—	—	—
Vasorelaxant	—	Yes35	Yes48	—	—	—

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

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

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.

Acknowledgements

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

Financial Disclosure: None.

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

Address correspondence to Aisling E. Courtney, MPhil, MRCP, Regional Nephrology Unit, Belfast City Hospital-Level 11, Lisburn Rd, Belfast BT9 7AB, UK.

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

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