NDT Advance Access originally published online on October 12, 2005
Nephrology Dialysis Transplantation 2006 21(2):330-336; doi:10.1093/ndt/gfi177
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Experimental Nephrology
Erythropoietin attenuates renal injury in experimental acute renal failure ischaemic/reperfusion model
1 Department of Physiology, 3 Department of Pathology, Aristotle University of Thessaloniki and 2 Department of Nephrology, General Hospital of Veria, Greece
Correspondence and offprint requests to: D. Tsakiris, Department of Nephrology, General Hospital of Veria, Greece. Email: dimtsak{at}otenet.gr
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Abstract |
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Background. Erythropoietin (EPO), originally identified for its critical role in promoting erythrocyte survival and differentiation, has been shown to exert multiple paracrine/autocrine functions. Protective effects of EPO have been demonstrated in various tissues and experimental models of ischaemia-induced injury. In the present study, we investigated the effect of EPO on an in vivo rat model of renal ischaemia/reperfusion (I/R) injury and the possible mechanisms implicated in the EPO-mediated anti-apoptotic action.
Methods. Male Wistar rats, subjected to renal ischaemia for 45 min, were administered either saline or EPO (500 U/kg, i.p.) 20 min prior to I/R. A sham-operated group served as the control. At 48 h of reperfusion, the renal dysfunction and injury was assessed by measurement of serum biochemical markers (urea, creatinine) and histological grading. Apoptosis was assessed by the TUNEL method and morphological criteria. Expression of Bax and NF-
B (p65) was also evaluated.
Results. High levels of serum urea and creatinine were identified at 48 h after ischaemia. The EPO-treated group had significantly lower serum and creatinine levels. Semi-quantitative assessment of the histological lesions showed that rats subjected to I/R developed marked structural damage, whereas significantly less tubular damage was observed in the EPO-treated group. I/R caused an increase in TUNEL-positive cells that was accompanied by morphological evidence of apoptosis. In the EPO-treated rats only a few scattered TUNEL-positive cells were observed. Up-regulation of Bax in the tubular epithelial cells and increased expression of NF-B was observed in the I/R-treated rats, while diminished expression of Bax and positive immunostaining of NF-B was observed in the EPO-treated rats.
Conclusion. Administration of EPO as a single dose before the onset of ischaemia produced a significant reduction in tubular injury, which was accompanied by a marked amelioration of renal functional impairment. The cytoprotective action of EPO against I/R injury seems to be associated with its anti-apoptotic action. Moreover, transcription factor NF-B is likely to play a pivotal role in the pathophysiology of I/R renal injury and might have a key role in EPO-mediated protective effects.
Keywords: acute renal failure; apoptosis; Bax; erythropoietin; ischaemia/reperfusion damage; NF-B; p65
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Introduction |
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I/R-induced acute renal failure (ARF) is a common clinical problem, which despite significant advances in critical care medicine is still associated with high morbidity and mortality [1]. The mechanisms underlying renal I/R are complex, including ATP depletion, accumulation of intracellular Ca2+ and reactive oxygen species, mitochondrial dysfunction, multiple enzyme systems activation and pro-inflammatory cytokine production. Although reperfusion is essential for the survival of ischaemic renal tissue, it causes additional cellular injury. Together, renal ischaemia and reperfusion initiate a multiple and interrelated sequence of events, resulting in the injury and eventually the death of renal cells as a combination of both apoptosis and necrosis [2].
EPO is a cytokine that was originally identified as the major regulator of erythroid precursor cells. However, increasing evidence suggests that EPO has broader functions independent of its effects on erythropoiesis. Recent in vitro and in vivo studies have demonstrated that EPO attenuates cell damage [3]. The favourable effects of the EPO-related changes are not fully known, although its anti-apoptotic, anti-oxidative and anti-inflammatory properties as well as its pro-angiogenic potential seem to be related to EPO-mediated protective effect. The biological effects of EPO are mediated by binding to its specific cell surface receptor (EPOR), and the presence of functional EPOR in renal tubular and mesangial cells has pointed to a potential autocrine or paracrine role for EPO in the kidney [4,5]. Furthermore, in recent in vivo studies subjected to cisplatin or to I/R injury, EPO enhanced functional and morphologic tissue recovery, mainly through its anti-apoptotic action [6–10].
The mechanisms through which EPO attenuates ischaemia-induced tissue damage are not fully understood. Binding to the EPOR seems to set in motion various intracellular pathways, including the mitogen-activated protein kinase (MAPK), Janus-tyrosine kinase-2/nuclear factor-B (JAK2/NF-B) and the phosphatidylinositol 3-kinase (PI3/Akt) signalling cascades [11]. Whether all these pathways are activated in all types of cells or their regulation is tissue specific has yet to be elucidated.
In the present study, we examined the effect of EPO on renal injury and also on the occurrence of apoptosis in an in vivo rat model of renal I/R injury. Futhermore, as most of the information about the role of the transciption factor NF-B on the EPO-induced protection comes from reports on CNS, we attempted to delineate whether NF-B is implicated in the EPO-mediated anti-apoptotic action in ischaemic renal injury.
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Material and methods |
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Renal ischaemia/reperfusion
Studies were performed on male Wistar rats weighing 200 to 250 g (n = 19). Rats received a standard diet and water ad libitum and were housed in a 12-h light/dark cycle. The animals were randomly allocated into three groups: (1) I/R-saline group, in which rats were subjected to renal ischaemia for 45 min (n = 7); (2) I/R-EPO group, in which rats were administered EPO (500 U/kg, i.p.) 20 min prior to I/R (n = 7); and (3) sham-operated group, in which rats were subjected to identical surgical procedure without occlusion of both renal pedicles and maintained under anaesthesia for the duration of the experiment (n = 5). Dose-dependent responses were not examined in our model. In previous studies, EPO was used in doses varying from 300–5000 IU/kg [6–8], and we choose a single rather low dose, which we expected to ensure the protective effect of EPO.
Rats were anaesthetized using chloral hydrate (4.5 g/kg, i.p.) and anaesthesia was maintained by supplementary injections of the same anaesthetic. Core body temperature was maintained at 37°C using a homeothermic table during surgery. The abdominal cavity was exposed via a midline incision, both kidneys were located and the renal pedicles were carefully isolated. Bilateral renal occlusion for 45 min was performed using non-traumatic vascular clamps. Occlusion was verified visually by observing blanching of the entire kidney surface. After the renal clips were removed, the kidneys were observed for a further 5 min to ensure colour change indicating blood reperfusion. Afterwards, 1 ml saline at 37°C was injected into the abdomen and the incision was sutured in two layers. The animals were allowed to survive for 48 h. Despite the severity of the damage observed at 48 h, the mortality of the animals was not significant (up to 10%) and was independent of the examined group. Preliminary data (not shown) suggest that the animals could survive up to 8 days following I/R. The experimental protocol was approved by the Local Ethical Committee, as it was in accordance with the 86/609 European Union Council order.
Measurement of biochemical parameters
Before the onset of the surgical procedure and at the end of the reperfusion period, blood samples (1 ml) were collected via the jugular vein. The samples were centrifuged (6000 rpm for 3 min) to separate serum. All serum samples were used for the measurement of biochemical renal parameters. Serum urea and creatinine levels were used as indicators of impaired renal function.
Histological evaluation and apoptosis assay
The kidneys were removed from the rats at the end of the experimental period and were cut in a sagittal section into two halves. Renal tissue was fixed in 10% buffered-formalin solution and embedded in paraffin. Paraffin kidney sections (5 µm) were prepared and stained with haematoxylin and eosin. Evaluation of renal injury was performed in a blinded manner by a pathologist and renal sections were scored with a semiquantitative scale designed to evaluate the degree of tubular necrosis. Injury was graded on a 5-point scale: 0 = normal kidney; 1 = minimal damage (<5% involvement of the cortex or outer medulla); 2 = mild damage (5–25% involvement of the cortex or outer medulla); 3 = moderate damage (25–75% involvement of the cortex or outer medulla); 4 = severe damage (>75% involvement of the cortex or outer medulla).
Sections adjacent to the haematoxylin and eosin-stained sections were processed for TUNEL [terminal deoxynucleotidyl transferase (TdT)-mediated uridine triphosphate nick end labelling] staining using an in situ apoptosis detection kit (R&D Systems). Briefly, 5 µm-thick paraffin sections were deparaffinized, permeabilized with proteinase K and incubated with a mixture of nucleotides and TdT enzyme for 60 min at 37°C. The signals were detected using streptavidin–horseradish peroxidase conjugate followed by the substrate diaminobenzidine (DAB). As a negative control, sections were incubated in the absence of TdT enzyme.
Apoptosis was also evaluated using previously defined morphological criteria [12]. These criteria include eosinophilic cytoplasm, cytoplasmic shrinkage, nuclear fragmentation, nuclear chromatin condensation, membrane-bound cellular blebbing and formation of apoptotic bodies.
Immunohistochemical localization of Bax and NF-B
Formalin-fixed, paraffin-embedded sections were used for immunohistochemical localization of Bax and NF-B. Antigen unmasking was performed by heating in a solution of 0.1 mmol/l citrate buffer, pH 6.0, using a microwave oven. Sections were incubated overnight with primary antibodies (1:200 for monoclonal Bax, 1:100 for polyclonal p65, Santa Cruz Biotechnology) at 4°C. After incubation with primary antibodies, the avidin–biotin-peroxidase complex method was used for detection of immunopositive cells (Dako). Immunoreactivity was visualized using the Sigmafast diaminobenzidine (DAB) tablet set (Sigma). Tissues were counterstained with haematoxylin. Negative controls consisted of each case in which the primary antibody was omitted.
The presence of p65 in the cytoplasm of renal cells was used as an indication that the NF-B heterotrimeric complex was still in its inactive form. In contrast, the localization of p65 in the nucleus indicated that the NF-B has translocated into the nucleus and was therefore able to activate transcription of NF-B-dependent genes.
Renal sections were scored for the presence of p65 in the nucleus of renal cells. Renal cells were quantitatively measured by counting at least 20 randomly selected high power fields (x400) in the cortex and outer medulla area. The final score obtained was expressed as percentage NF-B positive nuclei.
Statistical analysis
All values are expressed as mean±SEM. Statistical analysis was carried out using the SPSS 11.0 software. Biochemical parameters were evaluated by analysis of variance (ANOVA) followed by Bonferroni post hoc test. Student's t-test was performed for evaluation of scores of renal damage. P-values less than 0.05 were considered statistically significant.
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Results |
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Effects of EPO on renal dysfunction mediated by I/R
Animals that underwent renal I/R exhibited a 8-fold elevation in urea (381.2±6.3 mg/dl) and approximately 16-fold elevation in creatinine (6.7±1.4 mg/dl) concentrations compared to sham-operated animals (44±1.3, 0.4±0.01 mg/dl respectively) reflecting, thus, a significant degree of renal dysfunction (P<0.01). Serum urea and creatinine levels were significantly improved in rats pretreated with EPO. Compared to I/R animals, the administration of EPO decreased serum levels of urea (193.2±37.1 mg/dl) and creatinine (2.3±0.6 mg/dl) by 50 and 60%, respectively (P<0.01) (Figure 1A and B).
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Effects of EPO on the histological features of renal I/R
The characteristic histopathological features of ischaemic injury were readily evident at 48 h of reperfusion in kidneys obtained from I/R-treated rats compared with sham-operated rats. Specifically, the most severe and pronounced injuries were observed in the cortex and the outer stripe of outer medulla with a typical tubular necrosis pattern, which included widespread degeneration of tubular architecture, detachment of epithelial cells from the basement membrane, tubular cell necrosis, intratubular cast formation and luminal congestion with loss of brush border (Figure 2A). Taking into account the widespread degeneration of tubular architecture and the pronounced tubular necrosis pattern observed in this experimental model, it is quite difficult to distinguish the two types of tubules without being at the expense of the reliability of the results.
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In contrast, renal sections obtained from rats pretreated with EPO demonstrated marked reduction of the histological features of renal injury, consisting of more focal and mild characteristics of tubular necrosis (Figure 2B). Semi-quantitative assessment of the histological lesions showed a significantly higher score in the I/R-treated rats compared to the EPO-treated rats at 48 h of reperfusion (P<0.05, Figure 2C).
The presence of apoptotic cells was documented using the TUNEL assay (Figure 3A and B). There was a significant variability in the histology of tissue sections. The kidneys from animals that were subjected to renal I/R and exhibited severe tissue damage appeared to have increased number of TUNEL-positive cells. In contrast, the majority of the EPO-treated rats demonstrated a marked reduction of the histological features of renal injury, characterized as score 0 or 1. In these sections, only scattered TUNEL-positive cells were observed. However, for the demonstration of TUNEL assay in Figure 3B, we deliberately chose EPO-treated rats with a higher score [2,3], so that although they showed mild characteristics of tubular necrosis a marked reduction of TUNEL-positive cells was also obvious compared to the I/R-treated rats.
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TUNEL-positive cells in the kidneys from sham-operated rats and in the ischaemic samples, where TdT was omitted, were undetectable (data not shown). Morphologic assessment of apoptosis in the kidneys obtained from the I/R-treated rats showed decreased levels of apoptosis compared with the TUNEL assay assessment. In the EPO-treated rats, morphologic evidence of apoptosis was observed only in scattered tubular cells. Apoptosis-assessed morphology was not observed in the sham-operated animals.
Effects of EPO treatment on the activation and expression of NF-B and Bax in the kidney of rats subjected to ischaemia/reperfusion injury
The expression and localization of Bax and p65 were evaluated as indicators of apoptosis and activation of NF-B, respectively. In renal sections from the sham-operated rats, Bax expression was minimal in tubular epithelial cells. Obvious Bax staining was present in the damaged tubular epithelial cells. Renal sections from the I/R-treated rats exhibited markedly increased Bax expression of the distal and especially the proximal tubules. Low to moderate expression of Bax was observed in renal sections obtained from the rats pretreated with EPO (Figure 4A and B).
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Immunohistochemical staining for p65 was limited to the cytoplasm in the majority of renal cells in the kidneys obtained from the sham-operated rats, indicating that NF-
B was present in its inactive form. In the kidneys of rats subjected to I/R, there was staining for p65 in the nuclei of renal cells indicating translocation of NF-B to the nucleus. In rats subjected to I/R and pretreated with EPO, there was less staining for p65 in the nuclei of renal cells (Figure 5A and B). Scoring of renal sections for assessment of p65 present in the nucleus of renal cell nuclei revealed that more than half of all nuclei were positive for p65 in renal sections obtained from the rats subjected to I/R compared to kidneys obtained from the sham-operated rats (63.7±6 and 9.9±1.3%, respectively). This number was markedly reduced in renal sections obtained from the rats pretreated with EPO (29.3±10.5 vs 63.7 ± 6, P<0.05).
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Discussion |
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The present study provides evidence that administration of EPO protects the rat kidney in a model of severe I/R injury. According to our results, the administration of EPO as a single dose before the onset of ischaemia produces a significant reduction in tubular injury, which was accompanied by a marked amelioration of renal functional impairment as assessed by biochemical parameters. The cytoprotective action of EPO against I/R injury seems to be associated with its anti-apoptotic action. Moreover, transcription factor NF-
B is likely to play a pivotal role in the pathophysiology of I/R renal injury and might have a key role in EPO-mediated protective effects. Specifically, severe renal ischaemia for 45 min followed by reperfusion after 48 h caused significant renal dysfunction as assessed by a marked increase in the serum concentrations of urea and creatinine. Differences in the levels of biochemical parameters may be due to differences in experimental animals (Spague-Dawley vs Wistar) or differences in experimental conditions (i.e. temperature, duration of ischaemia). However, a similar degree of severity of renal injury to our model has been reported before [8]. Evidence of tubular injury was also supported by the histological scoring of renal injury. Based on morphological criteria and the TUNEL method, the form of tubular epithelial cell death was characterized as a combination of necrosis and apoptosis. These findings are in agreement with previous studies reporting that renal I/R initiates a complex cascade of events that eventually result in injury and subsequently in necrotic and/or apoptotic death of renal cells [13]. However, it is important to note that despite obvious evidence of apoptosis based on the TUNEL method, only a moderate increase in apoptosis has been identified at the same time point using morphologic criteria. This view is supported by previous findings suggesting that in the early time points after reperfusion, the amount of labelling did not indicate morphologically assessed apoptosis. A possible explanation for this is that free radical-induced DNA damage during reperfusion, which is repairable, is also detectable by enzymatic labelling [12].
In addition, in our study renal I/R resulted in increased expression of Bax protein in distal and especially in proximal tubular cells at 48 h of reperfusion, indicating that up-regulation of Bax protein could contribute in apoptotic cell death in severe renal I/R. Previous studies conducted in similar animal models of I/R renal injury have also shown that severe ischaemia leads to an increase in the Bax/Bcl-2 ratio suggesting that the fine balance between the activity of pro-apoptotic and anti-apoptotic Bcl-2 family members can determine cell survival and modulate the induction of apoptosis [12].
The effect of EPO on I/R-induced tubular cell death was investigated by quantifying apoptosis. We demonstrated that EPO inhibits apoptotic cell death in proximal and distal tubular cells as determined by DNA fragmentation, confirming, thus, previous data which suggested that inhibition of apoptosis is one of the most potential protective mechanisms of EPO. In rats subjected to I/R injury or to cisplatin-induced ARF, EPO treatment promoted functional and morphologic tubular regeneration [7–9]. More recently, Sharples et al. showed that a similar effect of EPO treatment in a rat model of renal ischaemia was induced by inhibition of caspase activation [6]. Furthermore, using 300 u/kg pre-ischaemia, pre-reperfusion and 30 min after reperfusion, they reported similar protective effect with the first two doses and no effect when EPO was given late after reperfusion [6], whereas, Patel et al., using 1000 u/kg 5 min pre-reperfusion and for 3 days prior to reperfusion, observed the best protective effect with the latter dose [7]. These observations could be of particular relevance for the potential clinical implications in humans.
Furthermore in our study, we showed that Bax expression on protein level is reduced and might be modulated by EPO in tubular epithelial cells. Previous studies have also shown that EPO, as a survival factor, mediates some of its action by shifting Bcl:Bax ratio towards a net anti-apoptotic effect, which favours cell survival [14].
In order to further clarify the anti-apoptotic mechanisms of EPO, we have also investigated the effect of I/R on the activation of NF-B in renal tissue with and without treatment of EPO. NF-B is a pleiotropic transcription factor implicated in the regulation of diverse biological phenomena, including apoptosis, cell survival and growth, innate immunity, cellular differentiation and the cellular response to stress, hypoxia and ischaemia [15]. The predominant form of NF-B is a heterodimer of p65 and p50 proteins. In unstimulated cells, NF-B is found in the cytoplasm in an inactive form associated with inhibitory IkBs proteins, which prevent it from entering the nucleus. Activation of NF-B involves the phosphorylation and degradation of IkBs as well as the passage of the transcription factor to the nucleus where it induces the expression of target genes [15]. The results presented here demonstrate that renal I/R leads to activation of NF-B, which, in accordance with previous studies, suggests that it might be a marker of injury linked to the pathophysiology of a variety of renal disorders, including I/R and its inhibition prevented in vivo cell apoptosis associated with renal I/R injury [15,16]. However, an anti-apoptotic role of NF-B has also been suggested. In vitro studies suggest that NF-B possesses a key role in the PI3-kinase–Akt pathway that acts as a survival signal in the regulation of apoptosis in mesangial cells [17]. It is already known from the recent literature that NF-B plays a key role in the EPO-mediated protective action in the nervous system. However, this effect could be tissue specific, and there is limited information that could support a similar role of NF-B in the ischaemic kidney.
It appears, therefore, that activation of NF-B may serve a dual role in inhibiting or promoting cell death pathways in a cell type- and stimulus-dependent manner [18].
Based on the information in the literature, however, it is not fully clear whether EPO-mediated anti-apoptotic effect is associated with NF-B activation in renal I/R injury. Recently, data provided by in vitro studies suggests that EPO-mediated protection against ischaemia-induced injury may involve cross-talk between JAK2 and NF-B resulting in an early (within 24 h of reperfusion) activation of NF-B signalling pathways [19]. According to our results, EPO administration did not result in NF-B activation at 48 h of reperfusion. However, it cannot be excluded that a transient increase of NF-B activation is implicated in the EPO-mediated protective signalling pathways, and it has been suggested that this phenomenon could have a protective role. Moreover, it has been assumed that a transient increase of NF-B activity may be responsible for the generation of the survival factors in cells that are destined to survive the ischaemic insult suggesting that the modulation of NF-B activation is multifactorial and rather complicated [20]. However, an EPO-triggering activation through a specific signal transduction pathway and regulatory mechanisms, such as types of activated NF-B hetero- or homodimers could ensure the transient activation of the transcription factor and subsequently promote its beneficial role. This might be one of the potential mechanisms underlying the protective action of EPO, which functions independently or in combination with other intracellular signaling cascades. Alternative protective mechanisms that might be activated downstream from the EPO/EPOR system could include the regulation of mitogen-activated protein kinase (MAPK) and the phosphatidyl-inositol 3-kinase (PI3K/Akt) system, as well as the increased expression of HSP70. Evidence to support these hypotheses is derived from observations in in vitro and in vivo studies of ischaemia-induced injury in the kidney [6,8,9].
Our data demonstrated that EPO administration in a single dose before the onset of ischaemia offered significant protection against ischaemia-induced renal injury. Based on these findings, EPO treatment may represent a novel therapeutic approach due to its capacity to preserve renal function and directly protect renal tissue. However, the mechanism by which EPO protects renal cells against I/R-induced injury is not fully elucidated. Improved understanding of EPO-mediated signalling cascade is needed in order to delineate the benefits of EPO therapy and incorporate its potential use into clinical practice in the future.
Conflict of interest statement. None declared.
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Accepted in revised form: 26. 9.05
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