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BASIC SCIENCE |
*Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff, Wales, United Kingdom; and Department of Biomedical Engineering, The Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Dr A. O. Phillips, Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN. Phone: 44-1222-748411; Fax: 44-1222-748470; E-mail: PhillipsAO{at}cf.ac.uk
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Abstract |
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is a potent stimulus for induction of HAS gene expression and HA synthesis. In this study, addition of IL-1 influenced neither HA cable formation nor CD44-mediated monocyte binding. Rather IL-1 led to an increase in intercellular adhesion molecule (ICAM)–dependent monocyte binding. Characterization of HA synthesis by addition of [3H]-glucosamine to cells at the time of stimulation demonstrated that increased HA in response to IL-1 was most apparent in the culture medium, while BMP-7 led to an increase in cell associated HA. Stimulation of cells with BMP-7 induced HAS2 mRNA expression and decreased the expression of Hyal1 and Hyal2. In contrast to BMP-7, IL-1 did not influence Hyal expression. The data presented in this manuscript provide insight into how alterations in HA synthesis in the renal cortex may be involved in modulation of the interaction between infiltrating inflammatory cells and resident cells. |
Introduction |
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In the normal kidney, HA is expressed in the interstitium of the renal papilla only, and alteration in papillary interstitial HA has been implicated in regulating renal water handling by affecting physiochemical characteristics of the papillary interstitial matrix and influencing the interstitial hydrostatic pressure (2). More recently, alterations in HA synthesis within the glomerulus of the kidney have been implicated in the pathogenesis of renal diseases such as diabetic nephropathy (3,4). Although HA is not a major constituent of the normal renal corticointerstitium, it is known to be expressed around proximal tubular cells (PTC) after renal injury caused by diverse diseases (5–8). Furthermore, increased deposition of interstitial HA has been shown to correlate with both proteinuria and renal function in progressive renal disease (9).
With the increasing awareness of the importance of pathologic changes in the renal interstitium, interest has focused on the role of cells, such as the epithelial cells of the proximal tubule, in the initiation of fibrosis. We recently examined the regulation of HA synthesis by renal PTC in vitro under conditions that mimic the diabetic state (10). These studies demonstrate that exposure of PTC to elevated D-glucose concentrations leads to nuclear factor–
B (NF-B)–dependent transcriptional activation of the HA synthase HAS2 and stimulation of HA synthesis. Similarly, HA synthesis is stimulated by addition of the proinflammatory cytokine IL-1. We have also characterized PTC expression of the HA receptor CD44 and demonstrated that stimuli inducing HA synthesis by PTC also regulate PTC-HA interactions, with increased binding and internalization resulting from posttranslational modification of CD44 by O-glycosylation (11). The functional significance of alterations in HA synthesis in the renal tubulointerstitium are however unclear. In vitro, HA oligosaccharides induce PTC chemokine and leukocyte adhesion molecule expression (12,13). These findings suggest a role for HA in the pathogenesis of renal interstitial inflammation. Inflammatory cell infiltrate, particularly monocyte/macrophage infiltrate, has been implicated in the pathogenesis of a wide diversity of renal diseases (14–16). Understanding the mechanism by which HA mediates inflammatory cell recruitment and its regulation, therefore, has important relevance to kidney disease. The first aim of the work presented in the current study was to examine the role of HA in monocyte binding by PTC.
Bone morphogenic protein-7 (BMP-7) is a member of the transforming growth factor– (TGF-) superfamily that is required during embryogenesis for normal kidney development (17). Its expression in the kidney has been suggested to be decreased in response to injury (18,19). Furthermore, administration of BMP-7 in models of chronic and acute renal failure results in a reduction of renal interstitial injury (20,21). The second aim of this study was therefore to examine the effect of BMP-7 on HA generation by PTC and to determine how this affects PTC monocyte interactions.
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Materials and Methods |
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U937 cells, originally derived from a human histiocytic lymphoma, were procured from the ATCC. The cells were grown in suspension culture in RPMI medium supplemented with L-glutamine and penicillin/streptomycin and containing 5% FCS. Cells were routinely subcultured at a 1:5 ratio three times per week. Although U937 cells are known to express some macrophage-like characteristics, cell binding was also assessed using human mononuclear cells prepared by dextran sedimentation and Ficoll-paque density separation, as described previously (23), to ensure general applicability of the results obtained using the U937 cells.
Immunocytochemistry
Immunocytochemistry was done on cells grown in eight-well glass chamber slides (Nunc; Life Technologies/BRL Life Technologies Ltd, Paisley, UK). Cells were grown to confluence and stimulated under serum-free conditions with either BMP-7 (Creative Biomolecules, Boston, MA) or IL-1 (R&D Systems Europe Ltd, Abingdon, UK) for 24 h. In control experiments, cells were incubated in serum-free medium alone. Culture medium was subsequently removed, and the cell monolayer washed with sterile phosphate-buffered saline (PBS). Cells were fixed by addition of 100% ice-cold methanol for 15 min at –20°C and permeabilized with 0.3% Triton X-100 for 30 min. Cells were blocked after fixation with 50% FCS for 1 h before a further washing step with PBS. For HA staining, a biotinylated HA-binding protein (b-HABP; 5 µg/ml) was then added (Seikagaku Corporation, Tokyo, Japan). For U937 staining, a purified monoclonal mouse anti-human CD68 antibody (Pharmingen: Becton Dickenson, Cowley, UK) was used (5 µg/ml). Slides were incubated with b-HABP and anti CD68 antibody at 4°C overnight. The slides were washed with PBS before incubation with fluorescence avidin-D (20 µg/ml; Vector Laboratories, CA) used for visualization of b-HABP and 20 µg/ml of Alexa Fluor 568 rabbit anti-mouse IgG (Molecular Probes, Eugene, OR) used for visualization of CD68, at room temperature for 1 h. After a final washing step, specimens were affixed to the slides in Vectasheild mounting medium (Vector Laboratories) and analyzed by confocal laser scanning microscopy (TCS-40 Leica Microsystems, Cambridge UK).
Assay for Leukocyte Adhesion
U937 cell adhesion was measured as described previously (24). Briefly, HK-2 cells were grown on 24-well culture plates until confluent. Stimuli were added to the cells 24 h before the assay. On the day of assay, U937 cells (up to 70 x 106 cells/ml) were labeled for 90 min at 37°C with 100 µCi 51Cr as sodium chromate (Amersham BioSciences, Chalford St Giles, UK). The labeled cells were washed three times with serum-free culture medium, counted on a hemacytometer, and resuspended to 106 viable cell/0.5 ml (as determined by Trypan blue dye exclusion). Incubation medium was removed from HK-2 cultures, and 106 monocytes were added to each well. The binding phase of the assay was done at 37°C for 1 h. All cultures were washed with cold medium before lysis by 1% Triton X-100. An aliquot was subsequently removed for quantitation of radiolabel. The number of the U937 cells bound per well was calculated from the initial specific activity (cpm/cell). Spontaneous release of chromium from U937 cells in control incubations without HK-2 cells was typically less than 10%.
The relationship between HK-2 cells and added monocytes was also visualized by light microscopy after 4',6-diamidino-2-phenylindole dihydrochloride hydrate (DAPI, Sigma-Aldrich) staining of cell nuclei. DAPI, at a final concentration of 5 µg/ml, was added to the slides for 1 h at 4°C before mounting with Vectasheild mounting medium. Slides were stored at 4°C until visualized (within 48 h).
Analysis of 3H-Radiolabelled Hyaluronan
In vitro [3H]-labeling of HA was performed as described previously (25). Briefly, growth-arrested confluent HK-2 cells were stimulated with recombinant IL-1 or BMP7 in the presence of 20 µCi/ml 3H glucosamine (Amersham Bioscineces) for 24 h. Supernatant samples were collected and treated with equal volume of 200 µg/ml pronase (Sigma-Aldrich) for 24 h at 37°C to analyze HA released into the culture medium (CM fraction). The remaining cell monolayers were incubated with 10 µg/ml trypsin (Sigma-Aldrich) in PBS for 10 min at room temperature to remove pericellular (protein-bound) 3H-HA (PB fraction) before addition of an equal volume of 100 µg/ml pronase for 24 h at 37°C. Finally, after trypsinization, 100 µg/ml pronase was added to the cell pellet for 24 h at 37°C to solubilize the remaining cells associated 3H-hyaluroanan (CA fraction).
Each of the fractions was subsequently passed over DEAE ion-exchange columns (Amersham Biosciences) equilibrated with 8 M urea (pH = 6) in Bis-Tris buffer. The columns were washed using 8 M urea buffer to remove low–molecular weight (MW) peptides and unincorporated radiolabel. HA was then eluted with 0.3 M NaCl urea buffer. Equal volumes of eluted HA were then precipitated by 3 volumes of 1.3% wt/vol potassium acetate in 95% ethanol in the presence of 50 µg/ml of each HA, heparin (Sigma-Aldrich), and chondroitin sulfate (Sigma-Aldrich) as co-precipitants. The precipitated HA was separated into two equal volumes, with one directly resuspended in 4 M guanidine HCl buffer and the other incubated with 1 IU Streptococcal hyaluronidase (ICN Biomedicals, Basingstoke, UK) at 37°C for 24 h before addition of 4 M guanidine HCl buffer pH6. Each sample was run through a Sephacryl S-500 column (Amersham Biosciences) before quantitation of radioactivity. The value of the hyaluronidase-treated portion subtracted from the non-hyaluronidase treated portion was taken as HA associated radioactivity.
Alteration in mRNA Expression
Expressions of mRNAs for HA synthases and hyaluronidases were determined by reverse transcription and the polymerase chain reaction (RT-PCR) using specific oligoneucleotide primers (Table 1) as described previously (26). PCR was done for various cycles (28–38) to ensure that amplification was in the linear range of the curve. After PCR, one tenth of the PCR reaction from both test and control (-actin) product were mixed and separated by flat bed electrophoresis in 3% wt/vol NuSieve GTG agarose gels (Flowgen Instruments Ltd, Sittingbourne, UK), stained with ethidium bromide (Sigma-Aldrich) and photographed. The negatives were scanned using a densitometer (Model 620 video densitometer; Bio-Rad Laboratories Ltd), and the density of the bands were compared with those of the housekeeping gene. Results were expressed as the ratio of the gene of interest to -actin normalized to the control value (the ratio in the unstimulated cells) of each experiment.
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Results |
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High-power confocal images also demonstrated coalescence of HA cables from numerous cells and suggested an association with the cell nucleus (Figure 2A). Using fluorescence microscopy, HA cables appeared to traverse cells (Figure 2B); by visualization of cell nuclei by staining with DAPI, HA cables could be seen in intimate contact with the nuclear area of cells it traversed (Figure 2, C and D).
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The nature of monocyte-PTC interaction was further examined by addition of radiolabeled monocytes to unstimulated confluent monolayers of HK2 cells (Figure 4). Bound radioactivity was reduced by either addition of soluble intercellular adhesion molecule (ICAM; R&D Systems Europe Ltd) or addition of CD44 antibody to the monocytes, although this was only statistically significant after CD44 blockade. Combined blockade of both ICAM and CD44 further reduced monocyte binding, thus suggesting that both HA-based interactions and ICAM-dependent interactions contribute to monocyte binding under unstimulated conditions. In contrast to the effect of CD44 blockade, removal of the HA cables by incubation with hyaluronidase before the addition of radiolabeled monocytes led to a significant increase in bound radioactivity, thus suggesting that HA cable–dependent monocyte binding may limit or block monocyte binding to cell surface ICAM.
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Quantitation of monocyte binding, after stimulation with BMP-7 for 24 h, confirmed that there was a significant increase in bound U937 cells at all doses of BMP-7 added (Figure 6A). After stimulation with BMP-7 (200 ng/ml), this represented a 118% increase of bound U937 cells over control; for 800 ng/ml BMP-7, it represented a 160% increase (P = 0.0001 for both). The increase in monocyte binding after stimulation with BMP-7 was attenuated by addition of monocytes in the presence of the blocking antibody to CD44 (Figure 6B).
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Induced HA Synthesis But Does Not Increase HA Cable Formation is a potent stimulus for HA synthesis as assessed by quantitation of HA in the cell culture supernatant of IL-1–treated PTC (10). We therefore sought to determine the effect of IL-1 on HA cable formation and monocyte binding in HK2 cells.
Stimulation of monolayers of HK-2 cells with IL-1 led to a dose-dependent increase in binding of 51Cr-labeled U937 cells. IL-1–stimulated adhesion was significantly greater than binding of 51Cr-labeled U937 cells to control monolayers of HK-2 cells at all doses. Il-1 at a dose of 1 ng/ml induced a 45% increase in bound U937 cells over control (P = 0.0012); at the highest dose of IL-1 used (100 ng/ml), a 76% increase in bound U937 cells was seen (P = 0.0001) (Figure 7A). In contrast to BMP-7–induced adhesion, IL-1–induced monocyte binding was not affected by the addition of a blocking antibody to CD44 (Figure 7B). Addition of monocytes to IL-1–stimulated monolayers of HK-2 cells in the presence of soluble ICAM resulted in inhibition of the IL-1–induced increase in monocyte binding (Figure 7B). Additionally, examination of HA in IL-1–treated and -untreated control cultures by confocal microscopy did not demonstrate any increase in the formation of HA cables (Figure 8C), but it suggested a reduction in cable formation compared with control (Figure 8A). Fluorescence microscopic examination of IL-1–stimulated monolayers demonstrated binding of individual U937 cells but no binding in chain-like configurations (Figure 7D).
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stimulation was performed by addition of [3H] glucosamine to cells at the time of stimulation to generate 3H-labeled HA. Supernatant samples were collected to analyze HA released into the culture medium (CM fraction). The remaining cell layer was treated with trypsin to remove pericellular (protein-bound) 3H-HA (PB fraction). Finally, the cell pellet after trypsinization was subjected to exhaustive protease digestion to solubilize the remaining cells-associated 3H-HA (CA fraction). The hydrodynamic size of the synthesized HA in each fraction was subsequently analyzed under dissociative conditions on Sephacryl S-500. The presence of HA in samples was confirmed by incubation with Streptomyces hyaluronidase. Analysis on Sephacryl S-500 of the samples from control HK-2 cells demonstrated that the majority of the labeled HA in all three extracts (CM, PC, IC fractions) appeared near the void volume and therefore was considered to be of high molecular mass (Figure 9). The cell-associated fraction did contain a smaller peak of lower-MW HA consistent with a pool of intracellular, partially degraded HA as previously reported (28). After addition of BMP7-, an increase in the amount of radiolabeled HA was seen in the supernatant (CM fraction), the pericellular protein bound PC fractions, and the cell-associated (CA) fractions. The increase in HA was, however, most apparent in the pericellular and cell-associated fractions. Furthermore in the cell-associated fraction, there was an apparent increase in the MW distribution of the second, lower MW peak.
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stimulation, there was also an increase in the amount of HA in all three of the cellular pools. However, in contrast with BMP-7–associated changes, IL-1 induced the largest change in the high-MW HA secreted into the cell culture supernatant (Figure 9).
Expression of HA synthases (HAS) mRNA in HK-2 cells was examined by RT-PCR. BMP-7 stimulation led to induction of HAS2 mRNA above that seen in the control cells (Figure 10A). HAS3 mRNA was constitutively expressed by HK-2 cells as previously demonstrated (10) and was not influenced by the addition of BMP-7 (Figure 10B). Examination of hyaluronidase expression was also examined by RT-PCR. After addition of BMP-7, there was a significant decrease in the expression of both HYAL 1 and 2 mRNA (Figure 10, C and D). As we have previously reported, stimulation with IL-1 also increased the expression of HAS2 mRNA, without affecting expression of HAS 3 mRNA (Figure 10, A and B). In contrast to the effect of BMP-7, stimulation with IL-1 did not influence expression of either hyaluronidase mRNA (Figure 10, C and D).
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and stimulate the secretion of tissue inhibitors of metalloproteinases (32,33). These observations therefore suggest that high-MW HA may be "anti-fibrotic," whereas, if unabated, the generation of low MW HA fragments may disrupt the normal balance between cells and matrix and contribute to the pathophysiology of chronic tissue inflammation and fibrosis. Fewer data are available on the effect of HA on renal cells
In this article, we have demonstrated that HA mediates binding of monocytes to PTC when HA coalesces into cable-like structures. These structures seem to originate from numerous different cells and form cables spanning several cell widths. HA cables present on unstimulated cells bind unstimulated monocytes, and their formation is upregulated by BMP-7. As a consequence of increased HA cable formation, we have shown that BMP-7 also increased HA-dependent monocyte binding. Increased HA cable formation after addition of BMP-7 was associated with induction of HAS2 mRNA, and an increase in newly synthesized cell associated HA was also observed. This would suggest a specific effect of BMP-7 on the assembly of pericellular HA structures. The inter-
-trypsin inhibitor (II) family are a group of serum protease inhibitors, and previous studies utilizing colonic mucosal smooth muscle cells have suggested that the heavy chains of II are critical to the formation HA-based cables (34). It was particularly noted that there was a marked attenuation of HA cable formation in the absence of serum. All our experiments were performed in the absence of serum. However, we have previously demonstrated that PTC express bikunin and H3 components of the II family constitutively (35). This may therefore explain the ability of PTC to generate stable HA-based cable structures in the absence of serum components.
The specificity of the effect of BMP-7 was confirmed by data demonstrating that IL-1, despite being a potent stimulus of HA synthesis, was unable to alter HA cable formation. IL-1 did however increase monocyte binding. This increase appeared to be unrelated to any alteration in formation of HA cables, but rather monocyte binding to the HK-2 cells was mediated by other leukocyte adhesion molecules, particularly ICAM. Importantly, these data provide evidence that not only the quantity, but also the structure of HA is crucial for leukocyte binding.
An important difference between BMP-7 and IL-1 in terms of their impact on HA turnover was their effect on hyaluronidase expression. We were able to demonstrate downregulation of hyaluronidase (hyal1 and hyal2) at the level of transcription with BMP-7, whereas IL-1 did not alter their expression. The change in the MW of the cell-associated HA after stimulation with BMP-7 is consistent with decreased intracellular degradation of HA due to reduced hyaluronidase activity. As yet, there are no antibodies available to confirm that this was also paralleled by a decrease in protein expression and enzyme activity, but it is interesting to speculate that this difference between BMP-7 and IL-1–mediated regulation of hyaluronidase may be a key in understanding their differential effects on HA cable formation. HA synthesis occurs at or close to the cell membrane, and the growing HA chain is extruded through the membrane into the extracellular space (36). We postulate that downregulation of hyaluronidase activity by BMP-7 allows HA to remain associated with HAS and that HA extruded through the cell membrane is anchored to HAS isoforms and associates with similarly anchored HA from neighboring cell thus forming cables. In contrast, when hyaluronidase activity is not decreased, as seen after addition of IL-1, extruded HA is cleaved at the cell surface and secreted into the surrounding environment. In our studies, this is reflected by the increased concentration of HA in the culture supernatant after addition of IL-1, while BMP-7 led to a much smaller increase of HA in the culture supernatant, presumably due to less HA cleavage and release.
Although BMP-7 was originally identified as a protein that induced bone and cartilage formation, with an important role in the morphogenesis of embryo and in postnatal life (37), it is also produced in kidney (37,38). Recent studies have shown that BMP-7 is able to prevent kidney damage in vivo in numerous animal models of disease. In models of renal ischemia, infusion of BMP-7 reduces severity of renal injury and suppresses inflammation by downregulation of intercellular adhesive molecules (20). Interstitial inflammation and fibrogenesis associated with unilateral ureteral obstruction (UUO) are also prevented in vivo by administration of BMP-7 at the time of UUO (21). BMP-7 promoted maintenance of tubular epithelial integrity in the same model. This is consistent with in vivo studies demonstrating counteraction of TGF-1–induced epithelial-to-mesenchymal transition and reversal of chronic renal injury in the nephrotoxic serum nephritis model (39). Finally in the streptozotocin model of diabetic nephropathy, BMP-7 therapy in vivo markedly ameliorated glomerular pathology, decreased tubulointerstitial volume, and reduced proteinuria (40). In vitro studies shed some further light on the mechanistic basis of the mode of action of BMP-7. In mesangial cells, it reduces TGF-1–induced extracellular matrix effects (41). Specific membrane-bound high-affinity BMP-7 receptors have also been characterized on adult rat kidney tubular cells (42), and in vitro in PTC, BMP-7 antagonizes TNF-–stimulated increases in expression of proinflammatory cytokines and chemokines (43). How then can we relate the ant-inflammatory and antifibrotic effects of BMP-7 with increased HA cable-mediated monocyte binding?
Binding interactions between leukocytes and other cells are best characterized in endothelial cells in which leukocyte integrins on their surface bind to their ligands such as ICAM-1 and VCAM-1 (members of the Ig super-family) (44). Similar mechanisms of binding have been demonstrated in resident renal cells such as PTC (45) and fibroblasts (23). Proximal tubular cells express the adhesion molecules ICAM-1 and VCAM-1, and upregulation of these adhesion molecules predict outcome in inflammatory renal disease (45). Interaction of infiltrating inflammatory cells with PTC through these adhesion molecules stimulate the generation of several cytokine cascades (46). It is likely that such as inflammatory loops, if not controlled appropriately, will turn into a chronic phase which leads to the development of progressive fibrosis characteristic of chronic renal disease. In this article, we have demonstrated that BMP-7–induced monocyte binding is distinct from IL-1–induced monocyte binding. We postulate that the HA cables keep the monocytes away from the proinflammatory receptors. This hypothesis is supported by demonstration of increased monocyte binding to unstimulated cells when HA cables were removed by hyaluronidase treatment before the addition of the U937 cells. In addition, previous studies have suggested that BMP-7 may also influence ICAM–leukocyte interaction by downregulation of ICAM expression in PTC (43). In an in vivo setting, this would reduce the impact of any infiltrating monocytes and prevent the development of a proinflammatory amplification loop, which may lead to progressive interstitial fibrosis.
This effect of cell-associated HA cables in which HA is predominantly of high MW is in marked contrast to the reported effects of soluble low-MW HA. Addition of low-MW HA is a potent stimulus for increased expression of ICAM-1 and VCAM-1 in tubular epithelial cells (13). Together with increased expression of chemokines after addition of fragmented HA to PTC (12), this suggests that secreted HA, particularly when partially degraded, enhances leukocyte adhesion and subsequent cell activation, providing an amplification loop for proinflammatory effects of cytokines such as IL-1. This reinforces the principle that high-MW HA generally represents the normal homeostatic state, whereas the generation of low-MW HA fragments signals a disruption of the normal homeostatic environment.
In conclusion, most renal diseases are characterized by progressive loss of renal function, which results in a pathogenetic mechanism that is independent of the original disease (47). This final common pathway is initially characterized by the triggering of interstitial infiltration of inflammatory cells, which trigger further tubular damage, and interstitial fibrosis, which correlates with the rate of progression of renal disease. This seems to hold true, even in what are considered to be non-inflammatory diseases such as diabetic nephropathy, with recent studies suggesting that macrophage-derived proinflammatory cytokines acting upon resident cells may represent key events in progressive nephropathy (14,48). The data presented in this article provide insight into how alterations in HA synthesis in the renal cortex may be involved in modulation of the interaction between infiltrating inflammatory cells and resident cells and furthermore suggest a mechanism by which the known antiinflammatory and antifibrotic effects of BMP-7 in renal disease may be mediated. We speculate that the presence of BMP-7 is an important determinant of the function of HA. Chronic renal impairment is associated with a relative deficiency of BMP-7 but increased HA in the kidney. Under these conditions, increased HA generation is unlikely to form HA-based cables and therefore may be contribute to the damaging fibrotic response. In the presence of BMP-7, however, the formation of cables is facilitated the consequence of which may be decreased interaction of infiltrating cells with cell surface adhesion molecules on the resident cells.
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References |
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1 synthesis by human cultured renal proximal tubular cells: the permissive role of platelet derived growth factor. Am J Pathol 147: 362–374, 1995[Abstract]
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