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From the Department of General Surgery,* Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Academic Hospital Maastricht and Maastricht University, Maastricht; and the Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Academic Hospital Maastricht, Maastricht, the Netherlands
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Abstract |
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Next to the classical and alternative pathway, the mannose-binding lectin (MBL)-pathway forms a third activation route of the complement system. Interestingly, whereas in rodents two forms of MBL are present (MBL-A and -C), in humans only one MBL form exists. The MBL-pathway is initiated by binding of MBL to cell surface carbohydrates. Subsequently, two serine proteases, MBL-associated serine protease-1 and -2 (MASP-1 and -2), are activated, cleaving C2 and C4 to form the classical pathway C3 convertase.10 In vitro work shows that complement activation after endothelial oxidative stress is mediated by the MBL-pathway, by showing that C3-deposition after oxidative stress is attenuated by inhibition of the MBL-pathway.11 Activation of MBL in this in vitro model is reported to be mediated by cytokeratin-1 which is up-regulated and expressed on the cell surface in hypoxic endothelial cells.12
In vivo, cardiac I/R in rats induces MBL-deposition.11 Moreover, inhibition of the MBL-pathway reduces postischemic myocardial reperfusion injury in rats. Anti-MBL treatment reduced infarct size and inflammation (neutrophil-infiltration and pro-inflammatory gene expression).13 These data indicate that the MBL-pathway plays an important role in complement activation in the course of I/R injury. This tempted us to study the activation and regulation of the MBL-pathway in the course of experimental renal I/R injury and clinical post-transplant ARF.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Monoclonal antibodies recognizing mouse MBL-A and -C were kindly provided by Dr. Jensenius (Aarhus University Hospital, Aarhus, Denmark). Mouse-anti-human MBL (clone 3E7) was kindly provided by Hbt (Uden, the Netherlands). Rat anti-mouse C1q was a gift from Dr. E. Kremmer (GSF-Forschungszentrum, München, Germany), rabbit anti-mouse C6 was kindly provided by Dr. N.R. Cooper (Scripps Research Institute, La Jolla, CA), rabbit anti-rat C9 by Dr. B.P. Morgan (University of Wales College of Medicine, Cardiff, UK). Goat anti-mouse C3 was purchased from Cappel (ICN Biomedicals, Aurora, OH). Secondary antibodies, peroxidase conjugated rabbit anti-goat, goat anti-rabbit and goat anti-rat IgG as well as Texas-red-labeled goat anti-rat IgG and FITC-labeled goat anti-rabbit IgG were purchased from Jackson (West Grove, PA). All other reagents were purchased from Sigma (St. Louis, MO).
Experimental Renal Ischemia-Reperfusion Model
Male Swiss mice weighing 20 to 25 g were obtained from Charles River Breeding Laboratories (Heidelberg, Germany). Animals were housed individually in standard laboratory cages and were allowed free access to food and water throughout the experiments. The studies were carried out under a protocol approved by the Institutional Animal Care Committee of the University of Maastricht. At the start of the experiments, mice were anesthetized with sodium pentobarbital (100 mg/kg i.p.). Body temperature was maintained at 39°C by a heating pad until animals recovered from anesthesia. Under aseptic conditions, a 1.0-cm long midline abdominal incision was made and ischemia was induced by applying a non-traumatic vascular clamp to the left renal pedicle for 15, 30, or 45 minutes. Subsequently, the wound was covered with cotton soaked in sterile phosphate-buffered saline (PBS). After removal of the clamp the left kidney was inspected for restoration of blood flow and the contralateral kidney was removed and stored for analysis. The wound was closed in two layers and 0.25% bupivacaine was applied topically for postoperative pain management. The animals were sacrificed at indicated time points after reperfusion (n = 6 per group). At the time of sacrifice, blood was collected and the left kidney and liver were harvested for analysis.
Human Renal Biopsy Material
As part of our clinical transplantation protocol, pre-transplant needle biopsies are routinely taken from all donor kidneys before start of cold machine-preservation (pre-transplant biopsy). Another biopsy is obtained after approximately 30 to 60 minutes of reperfusion during the transplantation procedure (post-transplant biopsy).
The biopsies evaluated in the present study were chosen based on post-transplant organ function. We studied heart-beating (HB) donor kidneys which are not subjected to evident warm ischemia and functioned immediately after transplantation (n = 2). Also non-heart-beating (NHB) kidneys were used, these organs suffer per definition from evident warm ischemia and often display post-transplant organ-failure.14,15 Pre- and post-transplant biopsies of ischemically injured NHB kidneys displaying a delayed graft function (n = 3) or primary non-function (n = 3) were analyzed.
For the studied kidneys there were no differences in the duration of cold storage (28 ± 3 hours) and no acute rejections were observed. All biopsies were immediately embedded in Tissue-Tek (EMS; Washington, PA) and snap-frozen in isopentane at –80°C. Biopsies are stored at –80°C until further processing.
Renal Histology
Cryostat sections (5 µm) of frozen murine kidneys were fixed with acetone and stained for complement factors C3 or C6 as reported previously,16 and for C1q, MBL-A and MBL-C. For MBL-A and -C as well as C1q staining, slides were immersed in PBS for 5 minutes and subsequently in 5% normal goat serum in PBS to block aspecific antibody binding. Slides were incubated for 1 hour at room temperature with the anti-MBL-A, -MBL-C or -C1q primary antibody in PBS with 0.1% bovine serum albumin (BSA). After three washes in PBS for 5 minutes each, slides were incubated for 30 minutes with the peroxidase-labeled secondary antibody diluted in the same buffer. After three washes in PBS, staining was visualized by 3-amino-9-ethylcarbazole (AEC) followed by hematoxylin counterstain. Finally, the slides were cover-slipped, and viewed with a light microscope. No significant staining was detected in slides incubated with rat IgG instead of the primary antibody indicating the absence of significant background staining.
Murine cryostat sections (5 µm) were also double-stained for MBL-A or MBL-C and complement factor C6. Briefly, slides were dried, fixed in acetone for 10 minutes, and air-dried. Slides were immersed in PBS for 5 minutes and subsequently in 5% normal goat serum in PBS to block aspecific antibody binding. Slides were incubated for 1 hour at room temperature with anti-MBL-A or -C in combination with anti-C6 primary antibody in PBS with 0.1% BSA. After three washes in PBS for 5 minutes each, slides were incubated for 30 minutes with the appropriate FITC-labeled and Texas-red-labeled secondary antibody diluted in the same buffer. After three washes in PBS, the slides were mounted using glycerol-PBS with 1,4-diazabicyclo(2,2,2)octane (DABCO) and 4,6-diamidino(2)phenylindole (DAPI), and viewed with an immunofluorescence microscope. No significant staining was detected in slides incubated with control rabbit serum and/or rat IgG instead of the primary antibodies indicating the absence of significant background staining or cross-reactivity.
Human cryostat sections (2 µm) were stained for MBL and F-actin. Briefly, slides were immersed in PBS for 5 minutes and subsequently in 5% normal goat serum in PBS to block aspecific antibody binding. Slides were incubated with anti-MBL primary antibody in PBS with 0.1% BSA for 2 hours at room temperature. After three washes in PBS for 5 minutes each, slides were incubated for 30 minutes with the appropriate FITC-labeled secondary antibody diluted in the same buffer with the addition of Texas Red-phalloidin that specifically binds to F-actin. After three washes in PBS, the slides were mounted using glycerol-PBS with 1,4-diazabicyclo(2,2,2)octane (DABCO) and 4,6-diamidino(2)phenylindole (DAPI), and viewed with an immunofluorescence microscope.
MBL-A and -C ELISA
Sandwich ELISAs were used to measure serum MBL-A and -C concentrations in mice subjected to renal I/R. These ELISAs were kindly provided by Hbt (Uden, the Netherlands).
Measurement of Renal and Hepatic MBL-A and -C mRNA Levels by Reverse Transcriptase-PCR
For measurement of renal and hepatic MBL-A and -C mRNA levels in the course of experimental renal I/R injury, total RNA was extracted from kidneys and livers using the SV Total RNA isolation system (Promega, Madison, WI) and treated with RQ1 RNase-Free DNase (Promega). Total RNA was reverse-transcribed using oligo (dT) primer and Moloney murine leukemia virus reverse transcriptase. cDNA samples were standardized based on the content of ß-actin cDNA as housekeeping gene. ß-actin cDNA was evaluated by performance of a ß-actin PCR on multiple dilutions of each cDNA sample. The amount of amplified product was estimated by densitometry of ethidium bromide-stained 1.2% agarose gels using a CCD camera and Imagemaster VDS software (Pharmacia, Uppsala, Sweden). Primers used for the amplification of murine ß-actin were: 5'-TAA AAC GCA GCT CAG TAA CAG TCG G-3' (sense primer) and 5'-TGC AAT CCT GTG GCA TCC ATG AAA C-3' (antisense primer). To determine renal and hepatic MBL-A and -C mRNA expression, PCR reactions with specific primers were performed using appropriate dilutions of the cDNA. The sequences of these primers were as follows: MBL-A, 5'-CCA AAG GGG AGA AGG GAG AAC-3' (sense primer) and 5'-GCC TCG TCC GTG ATG CCT AG-3' (antisense primer); MBL-C, 5'-GAC GTG ACG GTG CCA AGG G-3' (sense primer) and 5'-CTT TCT GGA TGG CCG AGT TTT C-3' (antisense primer). The following PCR conditions were used: MBL-A and -C, 95°C for 30 seconds, 56°C for 45 seconds, 72°C for 30 seconds; MBL-A, 35 cycles for kidney and 25 cycles for liver samples; and MBL-C, 40 cycles for kidney and 30 cycles for liver samples.
PCR reactions were performed in a total volume of 25 µl in PCR buffer (Perkin Elmer, Boston, MA), in the presence of 0.2 mmol/L dNTP (Pharmacia), 1.0 µmol/L of each primer, 0.3 mmol/L MgCl2, and 0.5 U Taq polymerase (Perkin Elmer). After separation on 1.2% agarose gel, the amplified product was visualized using a CCD camera and Imagemaster VDS software (Pharmacia).
Renal Myeloperoxidase Assay
To quantify the extent of renal neutrophil accumulation, renal MPO content was determined.17 In brief, tissue samples were homogenized in 0.5% hexadecyltrimethylammonium bromide in 50 mmol/L PBS, pH = 6.0, 0.17 g tissue/ml. After heat incubation (2 hours, 60°C) and three freeze-thaw cycles, myeloperoxide (MPO) content was measured in triplicate by incubating supernatants with tetramethylbenzidine (TMB) substrate in a 96-well sample plate (Costar, Cambridge, MA) followed by measurement of optical density (OD) at 450 nm. MPO activity was calculated per mg renal tissue by comparing OD of samples with a standard titration curve of horseradish peroxidase. Data were standardized with respect to wet/dry ratios of the assayed renal tissue and are presented relative to the amount of MPO present in the contralateral kidney.
Renal Function
Blood urea nitrogen (BUN) was measured in serum obtained 24 hours after reperfusion using a Urea 25 kit (ABX Diagnostics, Eindhoven, Holland) in a Cobas Fara autoanalyzer (Roche, Basel, Switzerland).
Statistical Analysis
Data are expressed as medians with inter-quartile ranges or means with SEM and statistical analysis was performed by Mann-Whitney U-test. P < 0.05 was taken to denote statistical significance.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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To investigate activation of the MBL-pathway in the course of renal I/R, we first examined renal deposition of MBL-A and -C by immunohistochemistry. In line with a previous report,18
in murine renal control tissue both MBL-A and -C are localized to glomeruli with a mesangial expression pattern, whereas the vasculature and tubular epithelium is negative (Figure 1A and F
, respectively). Renal warm ischemia of 15, 30, or 45 minutes without reperfusion did not induce any changes in MBL-A or -C expression as compared to healthy control tissue (data not shown). Warm ischemia of 15 minutes followed by reperfusion did not induce activation of the MBL-pathway (Figure 1, B and G)
. Longer renal ischemia of 30 minutes and, in particular, 45 minutes induced a rapid deposition of MBL-A and MBL-C to tubular and interstitial cells and in peritubular capillaries. These depositions were already detectable after 1 hour of reperfusion for MBL-C (data not shown) and after 2 hours of reperfusion for both MBL-A (Figure 1, C and D)
and MBL-C (Figure 1, H and I)
. MBL-A and -C depositions were most pronounced after 24 hours of reperfusion when tubular casts also stained positive for MBL (Figure 1, E and J)
. These data show that warm ischemia followed by reperfusion induces the activation of the MBL-pathway depending on the duration of warm ischemia.
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. Furthermore, we examined the kinetics of renal deposition of the complement factors C3 (common pathway of the complement cascade), C6 and C9 (both part of the membrane attack complex (MAC)). Ischemia-induced renal deposition of C3 started after 2 hours reperfusion, deposition of C6 and C9, was first observed after 12 and 24 hours of reperfusion, respectively (Table 1)
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Ischemia-Induced MBL-Deposition Co-Localizes with Renal Complement Deposition
An important question is whether activation of the MBL-pathway is involved in complement activation in the course of renal I/R. Therefore we determined whether MBL-deposition co-localizes with the deposition of complement factor C6 which is part of the MAC and has been shown to be essentially involved in renal I/R injury.4,7
For the first time, we demonstrate that MBL-deposition almost completely co-localizes with renal C6 deposition (Figures 2 and 3)
. First, it is shown that in healthy kidneys both MBL-A and MBL-C are present in glomeruli without C6 deposition (Figure 2, A and D)
. Next, in the early reperfusion phase (1-hour reperfusion), after 45 minutes renal ischemia MBL-C, in contrast to MBL-A, is deposited to tubular epithelial cells, whereas no C6 deposition is observed (Figure 2, B and E)
. In the late reperfusion phase (24 hours of reperfusion), both MBL-A and -C are deposited and appear to be located at the same sites as C6 deposition (Figure 2, C and F
, respectively). In Figure 3
, the co-localization of both MBL-A and -C with C6 after 24 hours of reperfusion is further examined. MBL-A (left panel) and C6 (middle panel) displayed complete co-localization (right panel). Also MBL-C (left panel) and C6 (middle panel) almost completely co-localized (right panel). However, some tubuli appear to stain positive for C6 without evident MBL-C staining (Figure 3
, bottom panel). These data indicate that activation of the MBL-pathway is involved in the initiation of complement activation and MAC formation induced by renal ischemia.
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Next, serum levels of MBL-A and -C were measured to investigate the effects of renal I/R on circulating MBL levels. In normal mouse serum (Swiss mice) MBL-A and MBL-C levels were 11.2 and 49.5 µg/ml, respectively, which is comparable to reported MBL-levels in other mouse strains.19
Interestingly, the serum levels of MBL-A increased gradually during reperfusion, leading to a significant twofold increase 24 hours after reperfusion (Figure 4A)
. This is in line with data from Liu et al19
showing that MBL-A is an acute phase protein combined with data from our laboratory that renal I/R induces an acute phase response.20
In contrast, serum MBL-C levels decreased after renal I/R leading to a significant halving after 24 hours of reperfusion (Figure 4B)
. Thus, serum levels of MBL-A and -C are differentially regulated in the course of renal I/R injury.
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To get more insight in the regulation of MBL-A and -C in the course of renal I/R injury we determined mRNA expression levels of both MBL-forms in kidney and liver tissue after renal I/R. First, both MBL-A and -C are expressed in healthy control kidneys as determined by RT-PCR (Figure 5A)
. Renal I/R induced an evident decrease of both renal MBL-A and -C mRNA levels at 2 hours reperfusion, which partially recovered for MBL-A at 24 hours of reperfusion (Figure 5A)
. Next, in normal liver tissue, MBL-A as well as MBL-C are expressed (Figure 5B)
. In the early reperfusion phase no changes in expression levels were observed, however, at 24 hours reperfusion MBL-A mRNA expression increased, in contrast to MBL-C levels, which decreased slightly (Figure 5B)
. The ischemia-induced changes in liver mRNA levels correlated well with serum MBL levels (Figure 4)
.
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Activation of the complement system plays an important role in ischemia-induced inflammation, characterized by the infiltration of neutrophils and organ failure.4,6,7
We therefore questioned whether the early ischemia-induced deposition of MBL would correlate with inflammation and organ failure in the course of renal I/R injury. As reported, renal I/R induced no deposition of MBL after 15 minutes of ischemia, moderate MBL-depositions after 30 minutes of ischemia, and evident MBL-depositions after 45 minutes of ischemia followed by 1 to 2 hours of reperfusion (Figure 1)
. Interestingly, the early deposition of MBL correlated with the ischemia-induced influx of neutrophils 24 hours after reperfusion. Whereas 15 minutes of ischemia did not result in the renal infiltration of neutrophils, 30 and 45 minutes of warm ischemia resulted in an increasing amount of infiltrated neutrophils (Figure 6A)
. Moreover, the early deposition of MBL correlated with organ failure observed 24 hours after reperfusion. Whereas 15 minutes of ischemia only induced a marginal increase in BUN-levels, prolonged ischemia of 30 and 45 minutes resulted in strongly elevated BUN-levels reflecting severe organ failure (Figure 6B)
. Thus, the early deposition of MBL correlates with the development of I/R injury characterized by renal inflammation and organ failure. These data also suggest that the deposition of MBL, which results in complement activation, may be potentially involved in the development inflammation and organ failure in the course of renal I/R injury.
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Finally, we determined whether the MBL-pathway is activated in human I/R injury by staining human pre- and post-transplant kidney biopsies for MBL. In normal human kidney no MBL could be detected as described by others.21
In line with our experimental data all pre-transplant biopsies were negative for MBL (Figure 7
, A0 to F0). Interestingly, post-transplant biopsies of transplanted NHB donor kidneys, which per definition suffer from warm ischemia before organ procurement, stained positive for MBL (Figure 7
, B1 to F1). In particular, glomerular staining was observed in such transplanted NHB grafts (Figure 7, B1 and C1)
. In contrast, transplanted HB kidneys (which do not suffer from evident warm ischemia) were negative for MBL (Figure 7A1)
. Strikingly, in transplanted NHB kidneys which did not function after transplantation (primary non-function), interlobular arteries and peritubular capillary walls, as well as tubular epithelial cells and casts, stained positive (Figure 7, D1 to F1)
, in contrast to delayed functioning grafts (Figure 7, B1 and C1)
. Double-staining of MBL with von Willebrand Factor (staining endothelial cells) shows that MBL is deposited on peritubular capillaries (Figure 7G)
.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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In humans, MBL deficiency is one of the most common immunodeficiencies, arising primarily from three single point mutations in codons 52, 54, and 57 of exon 1 in the MBL gene.25 These mutations prevent the assembly of fully functional multimeric protein, resulting in low serum levels of MBL. MBL deficiency predisposes to a broad range of serious bacterial, viral, and fungal infections as well as autoimmune disease.25,26 On the other hand, a recent report indicates that MBL-deficiency prevents complement activation and subsequent systemic inflammation in patients undergoing thoraco-abdominal aortic aneurysm repair, suggesting that MBL deficiency might be beneficial in conditions of pathophysiologic complement activation, such as ischemic injury.27
In renal disease, glomerular MBL-deposition is observed in glomerulonephritis, among others, primary and secondary IgA nephropathy, lupus nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, and anti-GBM nephritis.21,28-30 Recent work shows that the MBL-pathway is not activated in renal transplantation, however, in that study, only living donor recipients suffering acute humoral rejection were studied.31 In acute humoral rejection the classical pathway of complement activation is regarded to be the main activation route of the complement system.31,32 In the present study we show for the first time that the MBL-pathway is activated after transplantation of ischemically injured NHB donor kidneys in contrast to HB donor kidneys. This indicates that activation of the MBL-pathway is initiated on the basis of ischemic injury followed by reperfusion. In particular kidneys that did not function after transplantation (primary non-function) showed widespread MBL-depositions, located on glomeruli, large vessels, peritubular capillaries, tubular epithelial cells, and tubular casts, suggesting that the MBL-pathway might be essentially involved in post-transplant I/R injury. These clinical observations are supported by our experimental data, which show that the deposition of MBL is dependent on the duration of warm ischemia and correlates with postischemic inflammation and organ-failure.
Involvement of the complement system in experimental renal I/R injury was already reported in 1985 by Stein et al33 showing complement deposition in a rat model for renal I/R injury. Only recently, an active role in the pathophysiology of I/R injury was addressed to the complement system by Zhou and colleagues,4 showing that complement-deficient mice are protected against I/R injury. The complement system can be activated via three pathways: the classical pathway (activated by antigen-antibody interaction), the MBL-pathway (activated by mannose present on microbial surfaces), and the alternative pathway (activated by microbial products). All three pathways converge at the level of C3 activation, forming a C5-convertase, which activates C5. Activation of C5 results in the formation of C5a and C5b, the latter one being the first step in the formation of MAC. Both the formation of MAC as well as the generation of the anaphylatoxin C5a have been shown to mediate renal I/R injury.4-7 However, via which pathway(s) complement activation is initiated in the course of renal I/R injury is still unclear. Complement activation in the kidney has been attributed to the alternative pathway mainly by exclusion of classical complement activation. Park et al8 demonstrated that renal I/R does not induce IgG or IgM deposition. In concordance we did not observe C1q deposition in our experimental model. RAG-1 –/– mice subjected to I/R still showed renal complement deposition, indicating that renal I/R is not mediated via the classical pathway.8 Indeed, C4-deficient mice, in contrast to C3-deficient mice, were not protected against renal I/R injury.4 Moreover, Thurman et al9 showed recently that mice lacking a functional alternative complement pathway (factor B –/– mice) are partially protected against renal ischemic injury, showing that the alternative pathway plays an important role in the pathophysiology of renal I/R injury. In an experimental mouse model for renal I/R injury we show for the first time that renal I/R induces the activation of the MBL-pathway. In the healthy mouse kidney only glomerular mesangial cells stained positive as reported by others.18 After renal I/R both MBL-A and -C deposited to injured tubular epithelial cells. The site of renal MBL-deposition observed in the present study was similar to ischemia-induced C3, C6, and C9 deposition, as reported previously.7 Therefore, co-localization studies were performed to demonstrate that MBL-deposition precedes and co-localizes with complement activation. Our data show that MBL-deposition precedes C3 and C6 deposition and moreover that C6 deposition completely co-localizes with MBL-deposition. These data are in line with recent in vitro studies showing that endothelial hypoxia followed by re-oxygenation induces MBL-deposition which co-localizes with C3 deposition.11,34 In vivo, MBL-A deposition has been observed during the early phase of myocardial I/R in a rat model. Moreover, inhibition of MBL-A protected against myocardial I/R injury, attenuating C3 deposition, reducing infarct size and neutrophil infiltration.13 In combination with our experimental and clinical data showing that the deposition of MBL correlates with postischemic organ-failure, these studies indicate that the MBL-pathway of complement activation plays an active role in I/R injury. However, additional intervention studies are needed to unravel the precise role of this pathway in renal I/R injury.
How the MBL-pathway is activated in the course of I/R injury remains unclear. Recent in vitro work indicates that cytokeratin 1 is involved in activation of the MBL-pathway.12 The membrane expression of cytokeratin 1 is up-regulated after endothelial hypoxic stress and inhibition of cytokeratin-1 prevented endothelial complement deposition (MBL and C3).12 Whether cytokeratin 1 plays a role in complement activation in renal I/R injury in vivo remains to be established.
Taken together, in the present study we show for the first time that the MBL-pathway is activated in the course of experimental as well as clinical renal I/R injury. Moreover, the MBL-pathway precedes and co-localizes with complement deposition in the course of I/R. These data indicate that the MBL-pathway of complement activation is essentially involved in renal I/R injury.
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Footnotes |
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Supported by the Dutch Kidney Foundation, Grant C99.1840 (to W.A.B.) and by AGIKO Stipendium of The Netherlands Organization of Scientific Research (to B.d.V.).
Accepted for publication July 20, 2004.
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