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*Renal Unit, University Hospital, Gent, Belgium; Medical Department M (Diabetes and Endocrinology), the Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark; and Division of Endocrinology, Department Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
Correspondence to Dr. An De Vriese, Renal Unit, AZ Sint-Jan AV, Ruddershove 10, B-8000 Brugge, Belgium. Phone: +32-50-452202; Fax: +32-50-452299;
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, development of submesothelial fibrosis, and fibronectin accumulation in the peritoneum of diabetic animals. In conclusion, binding of AGE to RAGE increases the expression of TGF- and contributes to the development of submesothelial fibrosis. Neoangiogenesis and the resultant loss of ultrafiltration capacity are mediated by different pathogenetic pathways. E-mail: an.devriese@azbrugge.be |
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AGE have been detected immunohistochemically in the mesothelium, submesothelial stroma, and vascular wall of PD patients (3–5). Circumstantial evidence implicates AGE in the genesis of ultrafiltration failure (3–5). Peritoneal staining for AGE was associated with a higher permeability to various solutes (3,5). In another study, the degree of interstitial fibrosis and vascular sclerosis correlated with interstitial and vascular AGE accumulation, respectively (4). An inverse relationship was found between these peritoneal histologic changes and ultrafiltration volume (4). However, the exact pathophysiological role of AGE accumulation in the peritoneal membrane remains unknown.
The pathogenicity of AGE relates to their ability to form cross links that alter the architecture and mechanical properties of the extracellular matrix, resulting in increased rigidity and thickness. Another mechanism through which AGE exert their effects is the binding to specific cellular receptors with activation of signal transduction pathways, leading to the synthesis and release of cytokines and growth factors, including IL-1, PDGF, vascular endothelial growth factor (VEGF), and TGF-, expression of adhesion molecules, and induction of procoagulant factors (6). The best characterized of the AGE receptors has been termed the receptor for AGE (RAGE), although other AGE-binding structures have been described (6). Human peritoneal mesothelial cells have been reported to express RAGE in vitro (7), but the in vivo localization of RAGE in the peritoneal membrane in physiologic and pathophysiological conditions is unknown.
The aim of this study was to examine the contribution of AGE-RAGE interactions to the pathophysiological events observed in the peritoneal membrane exposed to high glucose concentrations present in PD solutions. A major hurdle in studying the effects of PD fluid in animal models is the inevitable interference of trauma and infection, which by themselves may cause fibrosis and neoangiogenesis (8). To circumvent these difficulties, we have previously used experimental diabetes as a model to study the mechanisms of glucotoxicity to the peritoneal membrane (9). Using the same model, we examined the effects of inhibition of the AGE-RAGE interaction with a neutralizing monoclonal anti-RAGE antibody (Ab) on the function and structure of the peritoneal membrane exposed to high ambient glucose concentrations.
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Neutralizing Monoclonal Anti-RAGE Ab
The preparation and characterization of the neutralizing monoclonal anti-RAGE Ab followed procedures described previously in detail for the preparation of other neutralizing monoclonal Ab (10). The human RAGE extracellular domain encompassing residues 23 to 340 (sRAGE) was expressed and purified from Escherichia coli using the pET thioredoxin system (Novagen, Madison, WI). Female 8-wk-old BALB/c mice were immunized, then boosted three times, 21 d apart, by intraperitoneal and subcutaneous injections of 100 µg of sRAGE protein in Complete Freund’s adjuvant for the primary immunization and an additional 50 µg of sRAGE in Incomplete Freund’s adjuvant for secondary immunizations. Each of the mouse Ab titers was measured with ELISA using 50 ng of rhRAGE coated on Immulon 4 96-well dishes overnight at 4°C. The dishes were blocked with 5% BSA in PBS for 2 h at room temperature. The anti-sera were diluted using 1/10 dilutions, starting at 1/100 to 1/100,000 dilutions, then incubated at room temperature for 2 h while shaking. After washing with PBS containing 0.05% Tween 20, and 3 washes with PBS, secondary Ab (goat anti-mouse gamma chain-specific, alkaline phosphatase-conjugated) was added at 1/2,000 dilution for 45 min at room temperature while shaking. After washing with TBS containing 0.05% Tween 20, and three washes with TBS, PNPP substrate was added for 1 h and absorbance was read at 405 nm. The mouse with the highest serum titer to rhRAGE was injected intravenously with an additional 30 µg of immunogen in PBS, 21 d after the last immunization. Three days later, spleen cells were harvested for production of hybridomas to rhRAGE using previously described techniques (11). The hybridoma cell line with highest Ab titer and neutralizing Ab activity was selected after cloning three to four times by limiting dilution in 96-well microtiter plates, then grown in a Cellmax Bioreactor (Spectrum; Rancho Dominguez, CA) using Dulbecco modified Eagle medium. Purified IgG was prepared by Protein A chromatography. The isotype (IgG3) and light chain composition (kappa) of the Ab were determined as described previously (10).
Characterization of Anti-RAGE Ab Neutralizing Activity
A NF-
B reporter-gene assay using N
-(carboxymethyl)lysine-modified human serum albumin (CML-HSA) as a ligand for the RAGE receptor was used to measure neutralizing activity of the monoclonal Ab. Details of the preparation of CML-HSA as well as the reporter gene assay have been published previously (12). THP-1 cells were seeded at 5 x 106 cells per 100-mm dish in 10 ml of serum-free medium (SFM) the day before transfection. Transient transfection was performed using the DEAE-dextran method as described previously (13). Cells were washed once with SFM and resuspended in 1 ml of the same medium containing 2 µg of NF-B-Luc reporter plasmid (Clontech, Palo Alto, CA) and 200 µg/ml of DEAE-dextran (Promega, Madison, WI). The cell-DNA mixture was incubated at room temperature for 20 to 30 min before washing, centrifugation, and resuspension into fresh SFM. Transfected cells were seeded into 96-well plates at 70,000 cells/well for recovery. After 24 h, cells were pretreated with 10 to 100 µg/ml anti-RAGE Ab for 1 h, then treated with 200 to 600 µg/ml CML-modified albumin for 1 to 6 h before the reporter assay. Equivalent amounts of cell lysates, normalized for total protein (Bradford protein assay; Bio-Rad, Palo Alto, CA), were used for measurement of luciferase activity. Luciferase assays were performed using the Steady-Glo luciferase assay system according to the manufacturer’s instructions (Promega), and luminescence was detected in a TopCount microplate scintillation counter using a single-photon monitor program (Packard Instrument Company, Meriden, CT).
Anti-RAGE Ab Serum Levels
To determine serum levels of the anti-RAGE Ab, serum samples were obtained after 6 wk of treatment. Binding studies were performed using a commercially available ELISA kit with the capture Ab being rat anti-mouse IgG3 (#553404; BD PharMingen, San Diego, CA). Briefly, individual wells of a 96-well plate were coated with 50 µl of 1 µg/ml capture Ab overnight at 4°C, blocked using heat-inactivated 10% FCS PBS containing 0.05% sodium azide overnight at 4°C, then washed three times with PBS. Anti-RAGE Ab standards (50 µl of 10, 2, 0.4, and 0.08 µg/ml diluted in 5% FCS/PBS) and plasma samples (50 µl of 1/25, 1/100, and 1/1,000 serum dilutions) were added to appropriate wells, placed on a shaker for 2 h at 22°C, then incubations were terminated by washing wells once with 400 µl of ice-cold PBS + 0.05% Tween 20 followed by four more rinses with 200 µl of ice-cold PBS. Biotinylated rat anti-mouse IgG3 (#553401, 0.5 mg/ml; BD PharMingen) diluted 1/500 in TBS + 5% FCS was mixed with an equal volume of ExtraAvidin alkaline phosphate (E2636; Sigma, St. Louis, MO) diluted 1/1,500 in TBS + 5% FCS for 15 min at 22°C, then 50 µl of the complex was added to each well. After shaking for 1 h at 22°C, each well was rinsed once with TBS + 0.05% Tween 20 and three times with TBS, followed by the addition of 100 µl of 4-methylumbelliferyl phosphate liquid substrate (M3168; Sigma) and fluorescence was measured at excitation 360 nm/emission 440 nm.
Urinary Albumin Excretion.
Rats were housed in metabolic cages for 24 h and the urine was collected. Urine samples were stored at -20°C until analysis. Urinary albumin concentration was determined by a rat albumin RIA as described previously (14), using rabbit anti-rat albumin Ab RARa/Alb (Nordic Pharmaceuticals and Diagnostics, Tilburg, The Netherlands) and globulin-free rat albumin for standard and iodination (Sigma).
Peritoneal Transport Studies
Peritoneal transport studies were performed as described previously (9). Rats were anesthetized with thiobutabarbital (Inactin; RBI, Natick, MA) in a dose of 100 mg/kg subcutaneously. The trachea was intubated, a jugular vein was cannulated for continuous infusion of isotonic saline, and a carotid artery was cannulated for blood sampling. The saline infusion rate was matched with diuresis to maintain euvolemia. After 30 min, a silicon catheter (Venflon; Becton Dickinson, Erembodegem-Aalst, Belgium) was inserted in the abdomen and 15 ml of a 3.86% glucose peritoneal dialysate solution (Dianeal; Baxter, Nivelles, Belgium) was infused. Plasma and dialysate samples were collected at 0, 30, 60, and 120 min, for determination of creatinine, urea, and glucose levels. Fructosamine and total protein levels were determined on the first plasma sample only. Dialysate cultures were obtained at the end of the dwell and animals were excluded from analysis if cultures were positive. After 120 min, the abdomen was opened by midline incision for collection of the dialysate fluid and for tissue sampling. The transport of low molecular weight solutes was evaluated by calculating the mass transfer area coefficient (MTAC) of urea and creatinine, using the Garred equation: MTAC = volumeout/dwell time x ln[volumein x concplasma ÷ volumeout x (concplasma - concdialysate end)] (15). The initial peritoneal concentration of urea and creatinine is set at zero. The Garred equation is a simplified approach to calculate MTAC, assuming that the reflection coefficient of the solute is zero and that the average solute concentration in the membrane equals the plasma concentration. The magnitude of the transport of small solutes is determined by the effective vascular surface area, which is dependent on the number of perfused peritoneal capillaries (16).
Histologic and Immunohistochemical Analyses
A sample of parietal and visceral peritoneum was obtained in each experimental animal, fixed in 4% neutral buffered formalin and embedded in paraffin. Sections 5 µm long were cut for histology and immunohistochemistry.
The degree of fibrosis was evaluated using a Picro Sirius Red staining F3B (Klinipath, Geel, Belgium). Sections were deparaffinized, rehydrated, and stained briefly with Giemsa. Subsequently, sections were washed and stained with the Sirius Red solution, resulting in a brick red staining of all fibrillary collagen. Morphometric measurements were made by a masked operator with a Zeiss Axiophot microscope and a computerized image analysis system (Zeiss, Oberkochen, Germany) at magnification x200. For each sample of peritoneum, two sections were analyzed. A camera sampled the image of the stained sections and generated an electronic signal proportional to the intensity of illumination, which was then digitized into picture elements or pixels. The digital representation of the tissue was analyzed with KS400 Software (Zeiss). Each pixel in a color image was divided into three color components (hue, saturation, and intensity). The threshold for each color component of the staining was defined and kept constant throughout the analysis. In a predefined area covering the tissue within 500 µm of the mesothelium, the Picro Sirius Red staining was measured and expressed as a percentage.
Vascular density was evaluated with an immunostaining for endothelial nitric oxide synthase (eNOS). Sections were deparaffinized, rehydrated, incubated in 3% H2O2 in PBS for 15 min to block endogenous peroxidase, and washed in 10% normal horse serum (Sigma) in PBS for 20 min to block nonspecific binding. They were subsequently incubated with the primary Ab (anti-human eNOS; Transduction Laboratories, Lexington, KY), a biotinylated IgG (Vector Laboratories, Burlingame, CA), and streptavidin-peroxidase, for 45 min each. 3.3'-diaminobenzidine (DAB) was used as the chromogenic substrate to visualize immunolabeling, resulting in a brown precipitate. The immunostaining for eNOS was quantified as described above. The tissue staining for eNOS was measured and expressed as a percentage. In addition, labeled blood vessels were counted as N per field.
The expression of TGF- was investigated using a rabbit anti-human TGF-1 (Santa Cruz Biotechnology, Santa Cruz, CA) as the primary antibody. The localization of RAGE was evaluated using a goat anti-human RAGE (Research Diagnostics, Flanders, NJ) as the primary antibody. The immunostaining procedure and quantification were performed as described above.
Immunoblotting for eNOS and Fibronectin
The remaining visceral peritoneum was harvested, snap frozen in liquid nitrogen, and stored at -80°C until use. Approximately 50 mg of peritoneal tissue was sonicated for 20 s in chilled 50 mM Tris, 1 mM EDTA, pH 7.5 buffer. Samples (100 µg protein per lane) of tissue homogenates were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE, 7.5% acrylamide) and transferred by electroelution onto nitrocellulose paper (Schleicher and Schuell, Munich, Germany). The blots were blocked overnight at 4°C in 5% nonfat milk and incubated for 12 h at 4°C with a monoclonal eNOS Ab (Transduction Laboratories) at a dilution at 1/1,000, or with a polyclonal fibronectin Ab (Biogenesis, New Fields, Poole, United Kingdom) in a dilution of 1/6,500. After washing in TBS-Tween (0.1%), the membranes were incubated with an anti-mouse IgG Ab (for eNOS) or an anti-rabbit IgG Ab (for fibronectin) conjugated with horseradish peroxidase (both from Pierce, Rockford, IL) for 1 h at room temperature in a dilution of 1/10,000 and 1/75,000, respectively. The bands were visualized by chemiluminescence (BioWest; UPV, Upland, CA) and quantified by a UPV BioImaging System (UPV).
Statistical Analysis
The data are presented as mean ± SEM. ANOVA and unpaired t tests were used as appropriate to test statistical significance. The significance level was set at P < 0.05.
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Expression was increased in the diabetic animals that were treated with control Ab, but not in those treated with anti-RAGE Ab. The staining was especially enhanced in the vascular endothelium, as well as in the mesothelium and fibrotic tissue (Figure 5, Table 2).
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, Table 2). Anti-RAGE Ab did not affect eNOS expression in diabetic rats (Figures 8 and 9, Table 2).
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and a submesothelial collagen and fibronectin accumulation. Functionally, high glucose exposure causes an increased small solute transport, indicative of an enlarged effective peritoneal vascular surface area and resulting in loss of ultrafiltration capacity. These functional and structural characteristics of the peritoneal membrane are similar to those found in patients on long-term PD, thus incriminating the high glucose concentrations in peritoneal dialysate in the development of these changes. The salient observation in this study is that inhibition of the AGE–RAGE interaction with neutralizing monoclonal anti-RAGE Ab prevented the upregulation of TGF- and the extracellular matrix accumulation, but had no effect on the neoangiogenesis and the resultant rapid small solute transport and ultrafiltration failure. RAGE is an integral membrane protein from the Ig superfamily and is the best characterized signal transduction receptor for AGE (6). RAGE is expressed in a variety of cell types, including endothelial cells, vascular smooth muscle cells, macrophages, mesangial cells, and neurons. One study confirmed mRNA production and expression of functional RAGE in human peritoneal mesothelial cells in culture (7), but the localization of RAGE in the peritoneal membrane in vivo has not been reported previously. RAGE expression is low during homeostasis, but is strikingly enhanced in conditions characterized by cellular activation, including diabetes, uremia, and inflammation (6,17). In this study, the expression of RAGE was greatly increased in the peritoneum of diabetic animals. It was mainly found in the mesothelium, submesothelial fibrotic tissue, and blood vessel walls. Antagonism of RAGE had no apparent adverse effects in control rats, commensurate with the low expression level of RAGE in these animals.
Several lines of evidence support the fibrogenic properties of AGE. In cultured mesangial cells and vascular smooth muscle cells, exposure to both high glucose concentrations and AGE induced extracellular matrix synthesis, as evidenced by increased production of fibronectin, laminin, or collagen (18–24). The effects of high glucose or AGE appear to be mediated by TGF-, because neutralizing anti-TGF- antibodies prevented the increased production of extracellular matrix components (19–23). Exposure to ambient high glucose concentrations also induced fibronectin production in human peritoneal mesothelial cells, with TGF- as a downstream mediator (25–27). The effects of AGE per se on extracellular matrix production in the peritoneal membrane are, however, less well understood. This study provides the first in vivo evidence for a pivotal role of AGE-RAGE interaction in high glucose-induced peritoneal fibrogenesis. Furthermore, the results point toward TGF- as a important downstream effector of the profibrotic effects of AGE-RAGE. The development of peritoneal fibrosis in the diabetic animals was associated with an upregulation of TGF- expression, and both phenomena were prevented by treatment with neutralizing anti-RAGE Ab. Interaction of AGE with RAGE and the resultant TGF-–mediated myofibroblast transdifferentiation contributed to interstitial fibrosis in diabetic nephropathy (28). It is tempting to speculate that a similar mechanism may be responsible for the high glucose-induced fibrosis in the peritoneal membrane.
AGE are known to upregulate VEGF expression (29–32) and have angiogenic properties that are mediated by VEGF (33). We have previously reported that VEGF is a key player in hyperglycemia-induced neoangiogenesis (9). It was thus tempting to speculate that AGE might be upstream mediators of VEGF-induced neoangiogenesis in the peritoneal membrane. In this study, however, inhibition of the AGE–RAGE interaction had no effect on vascular density, eNOS expression, small solute transport rate, and ultrafiltration capacity. Our results thus do not support a role for the AGE–RAGE interaction in peritoneal neoangiogenesis, but they do not exclude a potential effect of AGE on vascular proliferation through other actions, i.e., binding with other receptors or nonreceptor-mediated mechanisms. Alternatively, other pathways may mediate the high glucose-induced VEGF expression in the peritoneal membrane, including reactive oxygen species (34), protein kinase C (35), and reductive stress (10).
Inhibition of fibrosis with anti-RAGE did not portent significant improvement in the transport characteristics of the peritoneal membrane. The results are in line with the observation that decorin, a TGF--inhibiting proteoglycan, decreased peritoneal collagen content but did not improve the ultrafiltration rate in a rat model of peritoneal dialysate exposure (36). In contrast, angiostatin, an inhibitor of angiogenesis, significantly reduced peritoneal vascular density and increased net ultrafiltration (36). Taken together, these results support the tight link between peritoneal neoangiogenesis and ultrafiltration failure and the absence of prominent functional consequences of submesothelial fibrosis.
Streptozotocin-induced diabetes was used as an experimental model for chronic exposure of the peritoneum to high glucose concentrations, to avoid the difficulties associated with chronic dialysate infusion models. Although succeeding in this respect, the diabetes model also has limitations. In PD, the higher glucose load and the exposure to reactive carbonyl groups derived from the uremic state and the presence of glucose degradation products may result in different and accelerated AGE formation. Our results, therefore, need to be confirmed in experimental models combining chronic dialysate exposure and uremia.
In conclusion, exposure of the peritoneal membrane to high glucose concentrations results structurally in fibrosis and neoangiogenesis and functionally in increased transport of small solutes and ultrafiltration failure. Action of AGE through binding with RAGE, with TGF- as downstream mediator, seems to be central in the development of submesothelial fibrosis, whereas neoangiogenesis and the resultant loss of ultrafiltration capacity are mediated by different pathogenetic pathways.
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B transcriptional activation and cytokine secretion. Diabetes 50: 1495–1504, 2001 gene requires DNA sequences both proximal and distal to the transcription start site for tissue-specific induction. Mol Cell Biol 13: 1332–1344, 19931 stimulate fibronectin gene expression through a cAMP response element. Kidney Int 46: 1019–1024, 1994[Medline]
mediate collagen production by mesangial cells exposed to advanced glycosylation end products. Kidney Int 48: 111–117, 1995[Medline]
in cultured human mesangial cells. Nephron 79: 38–43, 1998[CrossRef][Medline]
–induced fibronectin in mesangial cells. Biochem Biophys Res Commun 296: 1356, 2002[CrossRef][Medline]
1 and fibronectin synthesis by peritoneal mesothelial cells. Kidney Int 59: 463–470, 2001[CrossRef][Medline]
. Nephrol Dial Transplant 16: 1885–1892, 2001This article has been cited by other articles:
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P = 0.06 versus control + control Ab. Data are given as mean + SEM.
