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King’s College London School of Medicine at Guy’s, King’s College and St. Thomas’ Hospitals, Department of Nephrology & Transplantation, Guy’s Hospital, London
1 Correspondence: Department of Nephrology & Transplantation, 5th Floor, Thomas Guy House, Guy’s Hospital, King’s College, London, SE1 9RT, UK. E-mail: steven.sacks{at}kcl.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: renal transplant • immune regulation • complement
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 2)
. Inappropriate activation of the complement cascade may result in self-injury, typically in immune-mediated disorders such as rheumatoid arthritis and systemic lupus erythematosus. In addition, non-immunological conditions may be crucially dependent on complement activation. These include ischemia reperfusion (I/R) injury of the heart, lungs, bowel, liver, and kidney (3
4
5
6
7)
.
The central complement component, C3, plays a pivotal role in complement activation leading to the production of terminal pathway effector products. C3 also has a number of direct proinflammatory and immunoregulatory functions. While most of the circulating C3 is produced by hepatic synthesis, smaller amounts are generated at extrahepatic sites (8)
. Local sources include stimulated and resting epithelial cells, endothelial cells, macrophages and neutrophils, which are capable of secreting classical and alternative pathway components (9
10
11
12)
. Despite this widespread potential for local synthesis, the functional relevance of the extravascular pool of complement has remained controversial. Recent research has suggested critical roles for local production of C3 at locations of microbial invasion (13)
and immune regulation (14
, 15)
. However, for the large majority of complement-mediated disorders, especially those with a non-immune basis, the importance of locally synthesized complement remains unclear.
Ischemia reperfusion injury is a significant cause of morbidity and mortality after stroke, coronary thrombosis, cardiopulmonary bypass, and hypovolemic organ failure in native and transplanted organs. Complement is one of a number of major proinflammatory mechanisms that are known to participate in the pathogenesis of such tissue damage (7
, 16
, 17)
. Although it is known that C3 mRNA is increased in ischemic organs such as the heart and kidney (18
, 19)
, the relative contribution of local and systemic complement in the pathogenesis of ischemic injury is obscure. This distinction is important not only because tissue specific differences in the regulation of complement synthesis at different locations (20)
could explain differences in organ sensitivity to reperfusion damage, but also because genetic variation in the expression of proinflammatory mediators is known to influence the magnitude of the inflammatory response at particular locations (21
, 22)
. In addition, targeted therapy may prove more successful than systemic depletion of complement if local synthesis is found to have a predominant role (23)
.
The present study sought to investigate the role of local synthesis of C3 in an established rodent model of complement-dependent I/R injury (16)
. Previous work in native kidney and transplanted kidney models has shown that I/R damage is mediated by the terminal components of the complement cascade, which in turn depends critically on the cleavage of C3 (7
, 23)
. We first investigated the level of expression of C3 in mouse kidney isografts after I/R insult, in particular to determine the influence of cold ischemia and reperfusion. We then explored the consequences of this local expression of C3 on the structural and functional integrity of the transplanted kidney, using an isograft model to avoid an immune response. We report an unexpectedly strong effect of the local pool of C3, which appears to be functionally distinct from the circulating pool.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 25)
. As C3–/– mice were produced using C57BL/6 (B6) parents with SV129 embryonic stem cells, progeny were backcrossed onto the B6 parental strain for eleven generations. Animals were maintained in specific pathogen-free conditions. Wild-type B6 controls were purchased from Harlan UK Ltd. (Bicester, UK). Female mice (6–7 wk old), were used throughout. All animal procedures were conducted in accordance with the Animals (Scientific Procedures) Act of 1986.
Murine kidney transplantation
This technique was adapted from an earlier method (26)
. Mice were anaesthetized by inhalation of oxygen and Enflurane (Abbot, Maidenhead, UK), and kept warm throughout the procedure. The donor left kidney was surgically removed along with a renal arterial patch and renal vein. The ureter was separated and cut close to the bladder. The kidney was then placed on ice for a period of cold ischemia lasting between 30 min and 4 h. The recipient native kidney on the right was then removed and microaneurysm clamps were placed over the aorta and inferior vena cava (IVC). After incisions in recipient aorta and IVC in preparation for anastomosis, the donor kidney was transplanted into the left iliac fossa of the recipient. An end-to-side anastomosis of the donor aortic patch and renal arterial stump was made to the recipient and the clamps removed. The animal was then observed to ensure revascularization of the transplanted kidney. The donor ureter was attached to the recipient bladder, then 0.5 mL of warm saline was placed into the body cavity and the animal was sutured closed. Recipients were allowed to recover in a heated chamber for 24 h.
Assessment of renal pathology
Formalin-fixed and paraffin-embedded sections (2 µm) were stained using the periodic acid schiff (PAS) reaction and examined in a blinded fashion by two experienced persons. From four coronal sections per animal, viewed at a magnification of x160, the percentage of tubules in the corticomedullary junction showing tubular epithelial necrosis was estimated. This used a well-established five point scale: 0, normal kidney; 1, <10% necrosis; 2, 10–25% necrosis; 3, 26–75% necrosis; and 4, >75% necrosis (27)
.
Immunochemical staining
Frozen sections (4 µm) were air-dried, then acetone fixed. The antibody used to detect C3d was a purified Ig fraction of rabbit anti-human serum which is cross-reactive with mouse C3d (28)
. This antibody is also capable of reacting with whole C3. Detection of bound antibody used FITC-conjugated goat anti-rabbit IgG. For ICAM-1 staining, primary hamster anti-mouse ICAM-1 was followed by HRP-conjugated goat anti-hamster IgG. The primary antibodies for C3d and ICAM-1 staining were purchased from DAKO, Cambridge, UK. Secondary, FITC-labeled and HRP-labeled antibodies were purchased from Jackson Laboratories (Bar Harbor, Maine, USA).
In situ hybridization
In situ hybridization was performed on frozen sections using the HybriProbe in situ hybridization assay kit (Biognostik, Göttingen, Germany). The mouse C3-specific oligonucleotide was derived from the published sequence (Accession number: NM_009778). Briefly, 4 µm sections were fixed in 4% paraformaldehyde on silanized slides (DAKO). Sections were prehybridized for 4 h, then hybridized for 16 h with FITC-labeled probe for C3 mRNA. Bound probe was detected by immunochemical staining using an alkaline phosphatase (AP)-conjugated F(ab') antibody fragment to FITC (DAKO) followed by the substrate mixture BCIP/NBT (DAKO). This resulted in blue/purple product at the site of hybridization. Positive staining was quantified using LUCIA image analysis software (Jencons-PLS, Forest Row, UK). At a magnification of x400, for each animal, 10 fields from two stained kidney sections were photographed. Areas of positive staining in each image were outlined, highlighted, and values computed.
Measurement of serum creatinine by mass spectrometry
Serum samples were stored at –70°C prior to measurement of creatinine. Standards and samples were prepared in wells of a 96-well plate (Semat International, St. Albans, UK), and mass spectrometry was performed by Hospital Services.
Conventional RT-PCR
cDNA was synthesized as described (29)
from frozen kidney samples. PCR was carried out with 2 µL of diluted cDNA (reflecting 0.2 µg of total RNA), 12.5 pmol of each 3' and 5' primer pair for C3 and ß-actin (as an internal control), in 25 µL of reaction buffer (Promega, Southampton, UK). The PCR cycle consisted of 1 min at 94°C, 1 min at 62°C, and 1 min at 72°C. Amplified PCR products were visualized after electrophoresis on 1.2% agarose gel containing ethidium bromide.
Real-time RT-quantitative PCR (RT-qPCR)
RT-qPCR was performed with an MJ Research PTC-200 Peltier Thermal Cycler and DyNAmo HS SYBR Green qPCR kit (MJ Bioworks, Espoo, Finland). PCR was set up in 96-well plates containing 10 µL of master mix, 2 µL of diluted cDNA (reflecting 0.2 µg of total RNA), 10 pmol of each 3' and 5' primer pair, either for C3 gene or GAPDH gene, in a 20 µL reaction volume. Amplification was performed according to the manufacturer’s cycling protocol and done in triplicate. Gene expression was expressed as 2-
(Ct) (30)
, where Ct is cycle threshold; (Ct) = sample 1 (Ct) – sample 2 (Ct); (Ct) = GAPDH (Ct) – C3 gene (Ct).
Statistical analysis
Results are expressed as arithmetic means (±SE). Statistical analyses between experimental groups were performed using unpaired Student’s t test and ANOVA with Bonferroni correction for multiple comparisons. A difference was considered to be significant when P< 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Intrarenal C3 mRNA expression is a function of cold ischemic time
Figure 1
shows the effects of varying the cold ischemic time (CIT) on the expression of C3 mRNA in WT isografts harvested from WT recipients at 48 h after transplantation. The level of C3 mRNA, as assessed by conventional and real-time PCR, increased in a manner dependent on the duration of cold ischemia between 0 and 240 min (Fig. 1A, B
). Cold ischemia for 30 min was sufficient to induce up-regulation of C3 after reperfusion. However, in sham-treated kidneys subjected to 30 min of ischemia without reperfusion, the level of C3 mRNA was not significantly increased above the level in normal kidney (Fig. 1A
). Thus the period of cold and warm ischemia alone was not sufficient to stimulate C3 transcription, but reperfusion in conjunction with ischemia was required to induce gene expression. The extent of C3d protein staining and degree of histological injury were also related to the CIT (Fig. 1C, D
and Table 1
). Our model therefore showed a clear relationship between cold ischemic insult and the extent of intrarenal C3 expression.
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Increase of C3 mRNA expression is dependent on reperfusion time
We next examined the effect of reperfusion time on the expression of C3 mRNA in the postischemic isograft. Here the period of cold ischemia was maintained at 60 min. As shown in Fig. 2
A, B, the level of C3 mRNA increased at 24 h and 48 h of reperfusion, compared with normal kidney or with control kidney treated with 1 h of cold ischemia and no reperfusion. Together, these data show that the duration of both cold ischemia and reperfusion influence the level of C3 mRNA in mouse kidney isografts. The quantity of immunoreactive C3d increased with the duration of reperfusion in a parallel manner (Fig. 2C
). These results agree with an earlier study of native mouse kidney, where the amount of C3 increased for at least 24 h after reperfusion had commenced (16)
. Thus, although the initiation of complement activation is a rapid event, complement deposition appeared to be a continuous process, at least for the first 24–48 h after transplantation.
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On the basis of these results, we used a CIT of 30 min in all subsequent experiments in order to determine the effect of C3 on a moderate amount of I/R injury.
Deficient local synthesis of C3 reduces postischemic acute renal failure
We examined the influence of local production of C3 on the severity of postischemic acute renal failure. After exposure of WT or C3–/– donor organs to 30 min cold ischemia, ischemic kidneys were grafted into WT recipients. The recipient’s remaining native kidney was removed at day 5 post-transplantation, so that subsequent measurement of serum creatinine reflected the renal function of the transplant. As shown in Fig. 3
A, WT donor isografts underwent reversible acute renal failure, with recovery of normal serum creatinine by day 12 post-transplantation. C3–/– grafts showed significant protection.
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Systemic deficiency of C3 is nonessential for postischemic acute renal failure
Next, we transplanted WT donor organs into C3–/– recipients, to establish if circulating C3 influenced the development of postischemic acute renal failure. In the experiment shown in Fig. 3B
, the severity of acute renal failure in C3–/– recipients was no different from that in WT recipients. Combining C3 deficiency of the donor kidney with C3 deficiency of the recipient failed to give further improvement of isograft function, compared with deficiency in the donor kidney alone (Fig. 3B
vs. Fig. 3A
). Thus, renal isograft function after prolonged cold ischemia was not influenced by circulating C3.
Tubular damage is dependent on local synthesis of C3
The proximal tubular epithelium at the junction of renal cortex and medulla is not only the main target of complement-mediated injury in the postischemic kidney (7
, 31
, 32)
, but also is an abundant potential source of C3 and other complement-activating factors (33)
. To explore the locality of intrarenal synthesis in ischemic isografts and its relationship with the area of tissue injury, we carried out two additional experiments.
In the first such experiment, we examined the ischemic transplant at 48 h after reperfusion, which coincides with the period of maximal histological injury reported in native kidney studies (7)
. In situ hybridization results are illustrated in Fig. 4
. These show a low level of C3 mRNA detection in normal mouse kidney tubular epithelial cells, with a substantial increase in the intensity of staining and number of positive tubule cross sections in ischemic WT isografts (mean area of stained tubules/section: 0.88±0.06 µm2 vs. 2.23±0.18 µm2; P<0.05). Tubular injury scores, based on counting the number of abnormal tubules with epithelial degeneration, thinning, shedding or necrosis, displayed marked protection of C3–/– isografts compared with WT control grafts (Table 2
).
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A second experiment examined transplants removed at 8 days postreperfusion, to correspond with the period of functional injury defined after native nephrectomy (Fig. 3)
. Creatinine measurement on day 8 post-transplantation confirmed that C3–/– transplants had significantly better preservation of renal function than WT transplants (28.6±3.0 µmol/L vs. 70.0±4.3 µmol/L; P<0.05). In contrast, C3–/– recipients were not protected from renal failure compared with WT recipients (creatinine 74.6±3.1 µmol/L vs. 70.0±4.3 µmol/L; ns). The antibody used for detecting activated tissue-bound C3 (C3d) is also capable of reacting with nonactivated C3. However, the dense basolateral staining of tubules is consistent with deposited C3d (Fig. 5
A). Furthermore, we detected no peritubular capillary thrombosis in our model, and it is therefore unlikely that the peritubular staining represents trapped intravascular C3. Peritubular C3 staining was much reduced in C3–/– grafts (Fig. 5A
) and there was a commensurate reduction in tubular damage compared with WT isografts (Fig. 5B
and Table 3
). The kidneys of C3–/– mice transplanted into WT recipients contained small amounts of glomerular complement, present in a mesangiocapillary distribution (Fig. 5A
). This suggests that circulating C3 had better access to the glomeruli than to the tubulointerstitium of these grafts.
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Up-regulation of ICAM-1 is dependent on local expression of C3
Intercellular adhesion molecule-1 (ICAM-1) is one of several factors increased in ischemic tissue and known to mediate inflammatory cell infiltration (18
, 34)
. We asked whether complement might play an intermediary role in the up-regulation of such factors. The results presented in Fig. 6
A confirm that I/R injury increases the expression of MHC class II, B7.2, CD40 and ICAM-1 in the graft, at 24 and 48 h after reperfusion. ICAM-1 expression was blunted at 48 h in the absence of C3 expression by the graft (Fig. 6A
), whereas the other immunoregulatory factors remained unaltered in the absence of local C3. That the level of expression of ICAM-1 is affected by graft expression of C3 but not recipient C3, is indicated in Fig. 6B
. This suggests that ICAM-1 function may be selectively dependent on a C3-mediated pathway.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, our data identified no demonstrable role for leukocyte production of C3 (11
, 12)
. Rather, our data suggest an important role for resident renal cells that are capable of producing C3 (36)
. Ischemic injury is known to up-regulate complement transcription in renal and cardiac tissue (18
, 19)
. We extend these findings in the kidney by showing a causal relationship between this local synthesis and postischemic acute renal failure.
The failure of circulating C3 to participate in complement-mediated reperfusion damage could be explained by the large molecular size of C3 (
180 kDa), which might limit its penetration through the peritubular capillary wall. Or, it could reflect the abundance of locally synthesized C3 in the renal extracapillary space. The finding of C3 in the glomeruli of deficient ischemic transplants was in contrast to the weak tubulointerstitial staining in these grafts. Given that the glomerular capillary wall has a unique fenestrated structure, it is possible that the recipient’s circulating C3 had open access to the glomerular extracapillary space, but was unable to penetrate the intact structure of the peritubular capillary endothelium.
Our study demonstrates a significant capacity for local complement synthesis in the postischemic kidney. Of the known cell types that potentially contribute to local synthesis, our study indicates that the tubular epithelium is the most relevant site. Constitutional and regulated expression lead to secretion of C3 from the basolateral surface of tubular epithelial cells (37)
, and this may result in a pool of C3 in the renal interstitium that expands in stressful conditions. Previous work has led to an estimate that renal inflammation increases C3 production in transplanted human kidney by 2-fold (38)
. In the present study, the expression of C3 transcript increased 10- to 100-fold above baseline after the induction of ischemia. We propose that the basal and expanded pool of renally synthesized C3 is sufficient and necessary for local complement activation, and underpins the accumulation of complement in the postischemic graft.
The mechanism of action of complement leading to postischemic reperfusion damage has already been investigated in detail. Mice with deficient terminal pathway components such as C6 exhibit marked protection from post-ischemic acute renal failure, implying that membrane insertion of complement plays a major role (7)
. It is also recognized that membrane insertion of complement into cultured tubular epithelial cells induces a proinflammatory phenotype with secondary release of vasoactive molecules and leukocyte activators (39
, 40)
, potentially contributing to inflammation in the interstitial space. Other work provides strong evidence of C5a acting on the renal tubule via cell surface receptor (41)
. Thus, receptor-mediated and receptor-independent mechanisms may both contribute to the tubular injury, with consequent recruitment of inflammatory cells and degranulation of leukocytes. The products of C3 cleavage (C3a and C3b) seem to have little direct importance for tubular injury in this model (7)
. It therefore appears that the main function of C3, once activated by the alternative pathway (32)
or possibly the lectin pathway (42)
after renal ischemia and reperfusion, is to drive the formation of C5a and C5b-9. In other words, in the context of renal reperfusion injury, local synthesis of C3 acts as a driver of the effector functions of C5a and C5b-9.
Neutrophils and lymphocytes recruited into the area of injury are thought to contribute to the pathogenesis of postischemic acute renal failure. The adhesion molecules ICAM-1 and P-selectin are essential for the migration of circulating leukocytes into inflamed sites (27
, 16)
. Our results suggest that tubular ICAM-1 expression subsequent to ischemia is regulated by a complement-sensitive mechanism. Whereas pathways for other molecular mechanisms of interaction with leukocytes (B7.2, CD40 and MHC class II) were unaffected by the absence of C3, the expression of ICAM-1 on renal tissue was C3-dependent. Inflammatory cytokines able to regulate ICAM-1 expression on tubule cells also modulate the synthesis of complement in these cells (18
, 43)
. More work is needed to clarify the possible mechanisms of interaction leading to enhanced ICAM-1 expression, and to determine if the effect on ICAM-1 involves a paracrine or autocrine effect of C3. In contrast to ICAM-1, the increase of P-selectin in ischemic mouse kidney is independent of complement (16)
.
Clinical studies show that prolonged cold ischemia and its manifestation as delayed graft function are associated with reduced 1-year kidney graft survival rates (44)
. Long-term graft survival is also reduced. In one large study of 27,096 kidney transplant recipients, delayed graft function without immunological rejection reduced the graft half-life from 12.9 to 8 years (44)
. Notwithstanding the difficulties in extrapolating from mouse to man, our present results indicate that elevation of C3 in response to prolonged CIT worsens the grade of postischemic damage. The clinical effect of CIT on delayed graft function may therefore, in part, be explained by complement. Inactivation of complement, and thus reduction of postischemic acute renal failure, may lead to a reduction of renal scarring with the possibility of better graft outcome (23)
.
The constituent cells of many vital organs (e.g., epithelium and endothelium, glial cells, astrocytes, myocytes, hepatocytes, fibroblasts, and keratinocytes,) are capable of producing complement components (8)
, especially in response to pathogenic stimuli (45)
. A role for local extracapillary production of complement is therefore feasible at other sites, in reperfusion injury and other inflammatory conditions such as systemic lupus erythematosus (46)
. Moreover, in the light of our results, targeted therapy could be more effective than systemic depletion of complement for the prevention of reperfusion injury. For example, the soluble human complement receptor sCR1 has been successfully targeted to activated endothelium by means of a P-selectin binding ligand, and found to be effective at preventing pulmonary reperfusion damage (47)
. Other research has led to the development of a membrane inserting tag combined with a recombinant CR1 fragment, which offers the possibility of localized inhibition of complement on donor kidney epithelium (23)
.
In conclusion, our data offer more definitive evidence of a role for the local synthesis of complement in the pathogenesis of renal transplant reperfusion injury. Our findings are consistent with a dual compartment model, in which the renal interstitium is the domain of local synthesis of C3, and where the role of circulating C3 appears to be redundant. This functional segregation into local and systemic pools of C3 may serve as a paradigm for the study of other non-immunological disorders, and strengthens the rationale for developing targeted therapeutic regulators.
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ACKNOWLEDGMENTS |
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Received for publication August 31, 2005. Accepted for publication October 19, 2005.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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