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Regular Articles |
From the Nephrology Research Unit *
and the
Departments of Pathology
and
Anesthesiology,
Mayo Clinic/Foundation,
Rochester; and the Department of Medicine,§
University of Minnesota, Minneapolis, Minnesota
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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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50%, reduces patient
survival to 4 years after its onset, and is associated with a median
patient age of 27 years at the time of death.4
Chronic
renal insufficiency and end-stage renal failure are thus critical
contributors to morbidity and mortality associated with sickle cell
disease.1-4 Renal involvement in sickle cell disease characteristically includes renal hypertrophy in the setting of prominent hemodynamic and vascular alterations.1-3 Such hemodynamic and vascular processes impose a spectrum of effects on renal perfusion at the whole-organ and regional levels within the kidney: at one end of this spectrum, and in the cortical circulation, renal plasma flow rates and glomerular filtration rates (GFRs) are increased, whereas at the other, perfusion of the medulla is diminished because of vaso-occlusive disease. Such alterations are incriminated in the pathogenesis of specific phenotypic features of sickle cell nephropathy: increased glomerular perfusion and filtration impose hemodynamically-mediated damage to the glomerular compartment, whereas medullary ischemia impairs concentrating ability and other aspects of tubular function, induces histological tubulointerstitial disease, and may provoke frank papillary infarction.1-3 Such vascular alterations—hyperemia in the case of the cortical circulation and ischemia in the case of the medullary circulation—may set in train inflammatory and fibrogenic processes that lead to progressive loss of renal function. Additionally, the kidney in sickle patients may be prone to intrinsic glomerulopathic processes manifested as focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis.1-3
Exploration of the mechanisms by which renal and other complications of sickle cell disease arise has been greatly facilitated by the recent availability of transgenic mice expressing sickle hemoglobin.5-7 The use of these models has provided insights into mechanisms underlying sickling in vivo and the mechanisms contributing to end-organ damage.5-7 These latter studies, for example, have revealed up-regulation of eNOS and iNOS in the kidneys of such mice,8,9 and have raised the possibility that such alterations may contribute to the development of renal complications of sickle cell disease.
The present studies represent characterization of changes in the kidney in a more recently described transgenic sickle mouse.10 This characterization includes, and focuses on, alterations in renal redox in this model. The rationale for examining renal redox resides in the recognition that the kidney in sickle cell disease is exposed to copious amounts of sickle hemoglobin. Because sickle hemoglobin is an unstable heme protein that may undergo scission to its heme and globin moieties,11,12 we reasoned that the kidney would be exposed to large amounts of heme, the latter representing a lipophilic pro-oxidant.11,12 In our examination of the involvement of oxidative stress in sickle cell nephropathy, we examined indices of oxidative stress along with heme content of the kidney.
We also examined expression of the redox sensitive enzyme, HO-1, as an index of oxidant stress.13-15 Heme oxygenase (HO) is the rate limiting enzyme in the degradation of heme, converting heme to biliverdin in the course of which iron is released and carbon monoxide is emitted. HO consists of three isozymes, HO-1 representing the isozyme that is induced by oxidative stress, heme, and other stressors; HO-1 thus provides a relevant and sensitive index by which to assess alterations in cellular redox.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This model is homozygous for deletion of mouse ß-globin, and
contains transgenes for human ßS- and
ßS-antilles-globins linked to the transgene
for human 
-globin.10
Studies were conducted in
aged-matched control and sickle mice comprising similar numbers of male
and female mice. Although the various studies of the kidney, in
aggregate, involved mice that ranged in age from 0.5 to 1.5 years, each
study was undertaken in similarly aged control and transgenic mice,
each group comprising similar numbers of male and female mice.
Determination of Plasma Creatinine Concentration and Urinary Protein Concentration
Renal function was assessed by the concentration of plasma creatinine, the latter determined on plasma derived from tail-vein blood samples and using a Beckman Creatinine Analyzer II (Beckman Instruments, Inc., Fullerton, CA).16 Urinary protein concentration was determined by the Coomassie method.
Lipid Peroxidation/Heme Content
Lipid peroxidation was assessed by the thiobarbituric acid reactive substance assay, as previously described.17 Heme content of whole kidney homogenate, and of various cellular fractions, was determined by the pyridine hemochromogen method, as previously described.17
Measurement of HO and Other Antioxidant Enzyme Activities
As described in detail in our previous study,18 HO activity was measured by the method of Pimstone and colleagues,19 catalase by the method of Aebi and colleagues,20 and glutathione peroxidase by the method of Lawrence and Burk.21
Northern Analysis
RNA from kidneys was extracted using the Trizol method (Life Technologies, Inc., Gaithersburg, MD). Twenty micrograms of total RNA from each sample were separated on an agarose gel and transferred to a nylon membrane.16 Membranes were hybridized overnight with 32P-labeled mouse HO-1 and mouse HO-2 cDNA probes.22 Autoradiograms were standardized, as previously described,22 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.
Detection of HO-1 by Immunoperoxidase
Kidney sections, derived at autopsy, were studied for the expression of HO-1 by immunoperoxidase. The patient was female, 47 years old, had a history of modest severity (average of three pain crises per year), and died of a massive thromboembolism during an acute painful episode. Normal kidney tissue from a nephrectomized specimen served as a control. Kidney sections were stained for HO-1 using a monoclonal HO-1 antibody (OSA-111; Stressgen, Victoria, BC, Canada) as the primary antibody, a polyclonal goat anti-mouse IgG as the secondary antibody (SAB-100, Stressgen), and diaminobenzidine as substrate for localization, as previously described in detail.16,22
Detection of HO-1 in Circulating Endothelial Cells (CECs) in Patients with Sickle Cell Disease
CECs were evaluated for expression of HO-1 using the methods we
have previously described in detail.23,24
Briefly, using
fresh whole blood anticoagulated with ethylenediaminetetraacetic acid,
we used immunomagnetic beads (Dynal, Oslo, Norway) coated with the
anti-endothelial cell monoclonal antibody, P1H12, to prepare a
CEC-enriched population of cells from the buffy coat.23,24
After transfer to slides, cells were fixed with 4% paraformaldehyde
and permeabilized with 0.4% Triton X-100. Cells were stained for HO-1
using a primary polyclonal antibody (SPA-895, Stressgen), followed by a
rhodamide-labeled goat anti-rabbit IgG (Jackson ImmunoResearch
Laboratories, West Grove, Pa). A negative control was provided by use
of an irrelevant primary antibody. Cells were scored as being
"negative" if they showed no increase in staining higher than that
of the negative control sample done in parallel. Cells were scored as
being "low positive" if their staining intensity exceeded that of
the negative control but was still less than that of the red
autofluorescence of the immunomagnetic beads in the preparation (Figure 9
, top left). Cells were scored as being "high positive" if their
staining was brighter than the bead autofluorescence (Figure 9
, top
right). Results are expressed as percentage of CECs being negative, low
positive, or high positive. Sufficient sample was evaluated for each
donor so that at least 10 CECs were screened per normal donor and at
least 20 CECs were screened per sickle donor; this difference is
accounted for by the much smaller number of CECs per ml of blood in
normal donors.23
These studies were conducted in four
healthy patients and in five patients with sickle cell disease.
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Buthionine-sulfoximine (BSO), an inhibitor of 
-glutamylcysteine
synthetase (the first step in glutathione synthesis), was administered
every 12 hours for 3 days to control and sickle mice (5 mmol/kg
i.p.).25
The kidneys were then harvested for the
assessment of thiol content and histological studies. Thiol content was
determined by the method based on the reduction of the Ellman reagent,
5,5'-dithiobis (2-nitrobenzoic acid), as previously
described.26
Statistics
Results are presented as means ± SEM. For statistical analyses, the Student’s t-test or the Mann-Whitney test was used as appropriate. Results are considered significant for P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The transgenic sickle mouse demonstrates increased kidney weight
and increased body weight as compared to control mice: both the
absolute kidney weight as well as the kidney weight factored for body
weight were increased in sickle mice (Table 1)
. The concentration of plasma
creatinine was significantly lower in sickle mice, and in light of the
greater body weight in sickle mice, this likely reflects a higher GFR
in the transgenic sickle mouse. Neither the urinary protein
concentration, nor the ratio of urinary concentration of
protein/urinary concentration of creatinine, was altered in sickle mice
(Table 1)
.
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. Sickle mice studied for up to
1.5 years of age did not develop progressive renal disease; in
particular, there was no significant segmental or global
glomerulosclerosis, interstitial fibrosis, atrophy of cortical or
medullary tubules other than that associated with aging in control,
aged-matched, mice.
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. The content
of heme—the latter representing a strong pro-oxidant species—in the
sickle kidney was uniformly increased in all cellular compartments
including whole-kidney homogenates, and in cytosolic, mitochondrial,
and microsomal fractions of the kidney (Figure 3)
.
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As HO is an antioxidant enzyme, we measured other antioxidant enzyme activity to determine whether such increase in HO activity was part of a more generalized antioxidant response. In this regard, catalase activity was unchanged in the sickle kidney (0.30 ± 0.02 versus 0.33 ± 0.02, k/mg protein; P = ns; n = 8 in control group and n = 10 in sickle mice) whereas glutathione peroxidase was reduced in the sickle kidney (589 ± 24 versus 509 ± 26, nmol/min/mg protein; P < 0.05; n = 8 in control group and n = 10 in sickle mice). Thus, the increase in HO activity does not seem to be part of a more widespread induction of antioxidant systems.
Increased HO activity may reflect induction of one of the HO isoforms.
We thus assessed the expression of HO-1 and HO-2 by Northern analysis.
HO-1 mRNA was increased some fivefold in the sickle kidney (Figure 4)
, whereas mRNA expression for HO-2, the
constitutively expressed isoform, was unaltered in the sickle kidney
(mean standardized densitometric values: 7.91 ± 1.38
versus 8.40 ± 1.22; P = ns;
n = 4 in control and sickle mice). Thus, induction of
HO-1 accompanies the presence of oxidative stress in the sickle kidney.
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: kidney thiol content was significantly
reduced in both groups, 50% reduction in control mice and 38%
reduction in sickle mice. Such administration of BSO did not have any
apparent histological effect in the kidney in control mice (data not
shown); however, such administration of BSO markedly exacerbated RBC
sickling in the kidney of the sickle mouse (Figures 6 and 7)
.
Medullary congestion was worsened in sickle mice treated with BSO as
compared with sickle mice treated with vehicle (Figure 6)
.
Additionally, and strikingly, BSO-treated sickle mice—but not
vehicle-treated sickle mice—exhibited extension of vascular congestion
and RBC sickling from the medulla (where they are normally exhibited,
and restricted to, in this unstressed transgenic sickle kidney) into
cortical capillaries, cortical arterioles, and glomeruli (Figure 7)
.
Thus, acute oxidative stress in the kidney, as induced by reduction in
kidney thiol content by BSO, exacerbates the sickling process that
occurs in the kidney.
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To determine whether HO-1 is induced in the kidney in patients
with sickle cell disease, we examined the expression of HO-1 in the
kidney obtained from a sickle patient who died after a massive
pulmonary embolus. The healthy human kidney does not express HO-1 as
shown in Figure 8A
. In contrast, the
sickle kidney exhibits diffuse and widespread brown staining, that was
HO-1 antibody-specific, in proximal and distal renal tubules (Figures 8B and 9)
, in interstitial cells (Figures 8B and 9)
, and in endothelial cells and in the smooth muscle cells in
the media of small arteries (Figure 10)
. Focal glomerular staining within
isolated cells was also observed (data not shown); however, the nature
of these cells—infiltrating mononuclear cells or mesangial
cells—demonstrating such staining awaits further investigation.
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, high positive staining for HO-1
in CECs was markedly greater in sickle patients as compared to healthy
controls.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In our characterization of this model, we demonstrate the presence of oxidative stress in the kidney. Our hypothesis that oxidative stress would occur in sickle cell disease drew on the notion that sickle hemoglobin, being an unstable heme protein,11,12 would undergo scission and thus provide increased amounts of heme in organs such as the kidney; heme is a recognized lipophilic pro-oxidant.11,12 Indeed, we demonstrate that heme content was markedly increased in kidney tissue, and is accompanied by increased amounts of lipid peroxidation. We suggest that such increased amounts of heme, especially in the setting of increased GFR, may further contribute to oxidative stress in this model. Increased GFR obligates increased sodium transport by the renal tubular epithelium, and as oxygen consumption is linked to the transport of sodium, increased sodium transport entails increased oxygen utilization;27 increased oxygen consumption, in turn, may lead to increased generation of reactive species.28
Oxidative stress in sickle cell disease may originate from other
sources including sickle erythrocytes and leukocytes: sickle RBCs may
themselves generate oxidants29
or stimulate endothelial
cells to generate oxidants30
; sickle RBCs rather than
normal RBCs adhere to polymorphonuclear leukocytes and activate the
respiratory burst.31
Systemic levels of cytokines are
elevated in sickle cell disease, even in the quiescent, crisis-free,
phase,32-36
and several of these cytokines, (for example,
tumor necrosis factor- and interleukin-6) are pro-oxidant. It is
also possible that, insofar as repetitive episodes of vaso-occlusion
occur in the sickle vasculature, and accordingly, expose tissues to
ischemia/reperfusion injury, attendant generation of oxidants may occur
through this mechanism.
To examine further the contribution of alterations in cellular redox to the complications of sickle cell disease, we decreased renal thiol content by administering BSO, an inhibitor of the synthesis of glutathione26 ; glutathione represents the dominant thiol in tissues. Using this manipulation, we demonstrate marked effects in sickle but not control mice: the kidney in the sickle mouse, exposed to the glutathione-depleting agent, BSO, exhibited extension of vascular congestion from the inner medulla (where RBC congestion is normally exhibited in this unstressed transgenic sickle kidney) into the outer medulla, cortical capillaries, and glomerular capillaries. It would be of interest to determine whether worsening of renal function accompanies this exacerbation of vaso-occlusive disease in sickle mice after the administration of BSO. It should also be pointed out that BSO likely induces oxidative stress in other tissues besides the kidney, including, and in particular, the erythrocyte. The content of GSH in erythrocytes is likely decreased after the administration of BSO. Thus, the precipitation of vaso-occlusive disease in the kidney in sickle mice after the administration of BSO, in all likelihood, reflects the integrated effects of oxidative stress induced in the kidney as well as oxidative stress induced in erythrocytes. We thus provide the novel observation that acute oxidative stress, as imposed by acute depletion of kidney thiol content, and in all likelihood, in conjunction with depletion of thiol content of erythrocytes, markedly predisposes to vaso-occlusive disease in the sickle kidney. Based on these findings, we suggest that oxidative stress may be a mechanism by which recognized inducers of sickle crisis—sepsis, in particular, which alters cellular redox—provoke acute vascular congestion and vaso-occlusive disease.
Vaso-occlusive processes occupy a pivotal position in the evolution of acute and chronic complications of sickle cell disease.37,38 Acute vaso-occlusive disease imposes ischemic/hypoxic, metabolic, and other insults, whereas recurrent cycles of occlusion and resolution of occlusion, subject tissues to ischemia-reperfusion pathobiology and other mechanisms that underlie chronic organ injury.37,38 A number of pathophysiological processes contribute to vaso-occlusive disease including sickling of erythrocytes, abnormal erythrocyte rheology, proinflammatory and procoagulant processes, activation of the endothelium, enhanced adhesion of erythrocytes to the endothelium, increased production of vasoactive substances, and aberrant vascular and neurohumoral responses.37,38 We provide the novel demonstration that alteration in cellular redox can markedly influence vaso-occlusive processes in sickle cell disease.
The presence of oxidative stress and increased amounts of heme in the sickle kidney led us to examine the expression of HO-1 in the sickle kidney. HO is the rate-limiting enzyme in the degradation of heme, and the isozyme, HO-1, is readily responsive to oxidative stress and heme.13-15 We demonstrate up-regulation of HO-1 in the sickle kidney accompanied by increased HO activity. This response seemed relatively specific because expression of the constitutive form of HO, HO-2, was unaltered, whereas activities of other antioxidant enzymes such as catalase and glutathione peroxidase were not increased. In complementary studies undertaken in a patient with sickle cell disease, HO-1 is also up-regulated in the kidney as evidenced by increased expression of HO-1 in renal tubular epithelial cells, in interstitial cells, and in the vasculature; focal staining for HO-1 was observed in glomeruli.
We speculate that such induction of HO may retard pathways of injury in the sickle kidney. HO activity degrades heme and assists in the cellular handling of iron;13-15 HO-1 is also an antioxidant and thereby protects against the injurious effects of oxidative stress.13-15 HO-1 facilitates the synthesis of ferritin that is the main chelator of iron in tissues.13,14 HO-1 generates carbon monoxide, and through this gaseous product, HO-1 promotes vasodilatation,39,40 the latter serving to retard the evolution of vaso-occlusive disease. HO-1 is anti-inflammatory through the recognized effects of its products, carbon monoxide and bilirubin;41,42 for example, carbon monoxide is a cytoprotectant,42 that can suppress proinflammatory cytokines such as platelet-derived growth factor and endothelin-1;43 bilirubin can attenuate adhesion of leukocytes to the venular endothelium.44 The particular importance of HO-1 in defending the kidney against heme protein-induced, acute or chronic nephrotoxicity is underscored by our recent studies in HO-1 knockout mice: HO-1 knockout mice demonstrate markedly worse renal injury and increased mortality as compared to wild-type mice when subjected either to the acute nephrotoxic effects of hemoglobin,16 or to the chronic inflammatory effects of repetitively administered hemoglobin.45 Drawing on these findings, we speculate that HO-1, induced in the sickle kidney, confers cytoprotectant, anti-inflammatory actions in the sickle kidney, the latter exposed as it is to large amounts of heme proteins.
Up-regulation of HO-1 in patients with sickle cell disease was not restricted to the kidney in that CECs in sickle patients demonstrate increased expression of HO-1. Recent studies of CECs have added new insights into the pathobiology of sickle cell disease.23,24,46 CECs are detected in sparse numbers in health, whereas in patients with sickle cell disease, the numbers of these cells increase fivefold in the steady state, and 10-fold in sickle crisis.23 Moreover, these endothelial cells display an activated phenotype as reflected by their up-regulation of adhesion molecules and selectins.23,24,46,47 Added evidence in support of an inflammatory systemic milieu in sickle cell disease is provided by elevated leukocytic counts which occur in these patients, and which correlate with their propensity to vaso-occlusive complications and overall mortality in sickle cell disease.48 These findings, in conjunction with elevated circulating levels of cytokines and acute phase response proteins,49,50 in aggregate, have led to the concept of sickle cell disease as a proinflammatory disease. Interestingly, many of the key participants in inflammation—chemokines, adhesion molecules, and selectins—may be induced by oxidative stress:51 oxidative stress occurring in sickle cell disease may thus contribute to the inflammatory phenotype of this disease. In this regard, the induction of HO-1, an antioxidant gene with anti-inflammatory properties,13-15 in CECs and in the kidney may offer a countervailing response in a proinflammatory milieu.
The lack of histological features of progressive renal injury in this transgenic sickle mouse model, despite the presence of vascular congestion in the medulla of the sickle kidney, merits comment. Firstly, it should be pointed out that only a subset of patients with sickle cell disease develop progressive nephropathy: this mouse model, in its basal unstressed state, may thus be more representative of those sickle patients who are not afflicted by progressive renal disease; as such, this transgenic sickle model may be particularly useful in examining mechanisms that provoke progressive renal injury in sickle cell disease. Perhaps, the severity of oxidative stress serves as a determinant of progressive renal disease; and in this regard, it is possible that exacerbation of oxidative stress in this transgenic sickle mouse by more sustained administration of BSO would eventuate in progressive renal injury. Secondly, the induction of HO-1 in the sickle kidney may mitigate chronic inflammatory processes that may otherwise occur. Relevant to this consideration is our recent demonstration that HO-1 knockout mice, but not wild-type mice, demonstrate marked tubulointerstitial inflammation when repetitively exposed to hemoglobin.45 Thirdly, models of chronic renal histological injury that are established in rats, when applied to mice, are often surprisingly mild and unprepossessing: for example, the remnant kidney model in the mouse fails to evince significant proteinuria, glomerulosclerosis, tubulointerstitial disease, or vascular sclerosis when followed for up to 44 weeks52 ; Mpv 17-deficient mice, which are characterized by heavy and sustained proteinuria, do not develop tubulointerstitial disease, when examined for up to 52 weeks of age.53
That expression of HO-1 is increased in sickle cell disease may also be relevant to the long-recognized but never explained finding of increased amounts of carboxyhemoglobin in patients with sickle cell disease.54 Carboxyhemoglobin levels reflect, in part, production of carbon monoxide,55 and the main biochemical system in the body that produces carbon monoxide is HO.13 We thus suggest that elevated levels of carboxyhemoglobin observed in sickle patients reflect induction of HO-1 in sickle cell disease.
CECs were used in examining expression of HO-1 for two main reasons: firstly, the use of these cells addresses the question whether cells other than the kidney in sickle cell disease express HO-1; secondly, the study of these cells has afforded insights in a number of other conditions attended by vascular injury including myocardial infarction, sepsis, traumatic vascular injury, and venous insufficiency.23,24,56 Given the presence of vascular injury in renal diseases in general, and the contribution of vascular injury to the morbidity and mortality associated with renal diseases, the study of CECs merits consideration as an approach in the investigation of vascular injury in renal diseases.
In summary, alterations in cellular redox occur in the sickle kidney. Such redox alterations, we posit, contribute to vascular pathobiological processes and inflammatory pathways that conspire in the pathogenesis of sickle cell nephropathy. These redox alterations are countered by the induction of HO-1, a system that, quite remarkably, possesses attributes that may oppose many of the pathogenetic mechanisms underlying renal and other complications of sickle cell disease.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health grants HL-55552 (to K. A. N. and R. P. H.), DK-47060 (to K. A. N.), DK-16105 (to J. P. G.), and HL-53524 (to Z. S. K.).
Accepted for publication December 13, 2000.
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 M. Aslan, T. M. Ryan, T. M. Townes, L. Coward, M. C. Kirk, S. Barnes, C. B. Alexander, S. S. Rosenfeld, and B. A. Freeman Nitric Oxide-dependent Generation of Reactive Species in Sickle Cell Disease. ACTIN TYROSINE NITRATION INDUCES DEFECTIVE CYTOSKELETAL POLYMERIZATION J. Biol. Chem., January 31, 2003; 278(6): 4194 - 4204. [Abstract] [Full Text] [PDF]
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M. S. Segal, A. Bihorac, and M. Koc Circulating endothelial cells: tea leaves for renal disease Am J Physiol Renal Physiol, July 1, 2002; 283(1): F11 - F19. [Abstract] [Full Text] [PDF]
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F. A. D. T. G. Wagener, A. Eggert, O. C. Boerman, W. J. G. Oyen, A. Verhofstad, N. G. Abraham, G. Adema, Y. van Kooyk, T. de Witte, and C. G. Figdor Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase Blood, September 15, 2001; 98(6): 1802 - 1811. [Abstract] [Full Text] [PDF]
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