in-depth review - peritoneal dialysis international

Recent advances in the field of glycobiology have exposeda multitude of biological processes that are controlled orinfluenced by proteoglycans, in both physiological andpathological conditions ranging from early embryonic de-velopment, inflammation, and fibrosis to tumor invasionand metastasis. The first part of this article reviews the bio-synthesis of proteoglycans and their multifunctional rolesin health and disease; the second part of this review focuseson their putative roles in peritoneal homeostasis and peri-toneal inflammation and fibrosis in the context of chronicperitoneal dialysis and peritonitis.

Perit Dial Int 2007; 27:375–390 www.PDIConnect.com

KEY WORDS: Proteoglycans; glycosaminoglycans;perlecan; decorin; biglycan; syndecan; peritoneal in-flammation; peritoneal fibrosis.

Peritoneal dialysis (PD) is an effective form of renalreplacement therapy and was introduced over three

decades ago. Despite its success, technique efficacy isdependent on the structural and functional integrity ofthe peritoneum. In many patients, peritoneal fibrosisand neoangiogenesis leading to increased permeabilityand ultrafiltration failure are observed (1). Compellingevidence suggests that the bioincompatible nature of PDsolutions is the single most important factor compro-mising the peritoneal membrane’s integrity and patients’longevity on PD. Established PD patients are exposed to

Peritoneal Dialysis International, Vol. 27, pp. 375–390Printed in Canada. All rights reserved.

0896-8608/07 $3.00 + .00Copyright © 2007 International Society for Peritoneal Dialysis

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IN-DEPTH REVIEW

PERITONEAL PROTEOGLYCANS: MUCH MORE THAN GROUND SUBSTANCE

Susan Yung and Tak Mao Chan

Department of Medicine, University of Hong Kong, Hong Kong

Correspondence to: S. Yung, Department of Medicine, Room302, New Clinical Building, Queen Mary Hospital, PokfulamRoad, Hong Kong.

[email protected] 25 March 2007; accepted 18 April 2007.

2200 – 7000 L of PD fluid per year, fluid in which glucoseis used as the conventional osmotic agent since it is in-expensive, safe, and easily metabolized to provide themain energy source in the body (2). In order to generatean osmotic drive, the glucose concentration must exceed15 – 40 times the physiologic concentration, and evenafter intraperitoneal equilibration, its concentrationremains 6 – 16 times that of physiologic concentrations.Constant exposure of the peritoneum to unphysiologicglucose concentrations results in pathologic distur-bances that are normally associated with diabetes mel-litus and include reduplication of the basementmembrane, cell hypertrophy, increased synthesis oftransforming growth factor beta-1 (TGF-β1) and matrixcomponents, and increased basement membrane perme-ability (3–9). Such detrimental changes may in part beinfluenced by the altered synthesis of proteoglycans(PGs), macromolecules that are ubiquitous to almost allmammalian cells.

Are PGs expressed in the peritoneal membrane? Ul-trastructural studies using ruthenium red have high-lighted the presence of anionic sites on the surface ofmesothelial cells and the underlying basement mem-brane (10,11). This electronegatively charged barrier wasshown to modulate the transport of proteins across theperitoneal membrane, since loss of anionic charge dueto either peritonitis or chemical neutralization resultedin an observed increase in the permeability of the peri-toneum to plasma proteins (12,13). While the chemicalnature of these anionic sites remains to be fully eluci-dated, glycosaminoglycans (GAGs) and PGs, at least inpart, account for the ruthenium staining since thesemacromolecules are synthesized and secreted by human

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YUNG and CHAN JULY 2007 – VOL. 27, NO. 4 PDI

peritoneal mesothelial cells (HPMCs) and have beenidentified as constituents of spent PD fluids (5,14–17).

This review will describe the complex chemical natureof PGs and their roles in cell growth, inflammation, an-giogenesis, and fibrosis in disease in general, but withspecific emphasis on the peritoneum during PD. Specifi-cally, this review will focus on the functional propertiesof perlecan, syndecan-1, decorin, and biglycan, PGs thatare predominantly synthesized by HPMCs in vitro. Read-ers should refer to a separate article in the PeritonealDialysis International In-Depth Review series relating tothe role of hyaluronan in the peritoneum (18).

PROTEOGLYCANS

Proteoglycans are complex macromolecules compris-ing a core protein to which one or more GAG chains areattached (19). While ubiquitous in almost all mamma-lian cells, PGs are most prominent in the connective tis-sue. They occupy highly strategic positions, including cellsurfaces, basement membranes, and the extracellularmatrix (ECM). Although previously described as muco-polysaccharides and ground substances, and thought toplay a passive role primarily as space fillers necessaryfor the orientation and organization of the ECM, there isnow compelling evidence that they are dynamic compo-nents of the cell or ECM, whereby they control a plethoraof biological processes, including cytokine andchemokine production, leukocyte recruitment, seques-tration and storage of growth factors in the extracellu-lar milieu, regulation of wound repair, and development(20–26). The diversity of PG functions lies in the com-plexity of their structure. Pathological disorders in whicha significant amount of tissue remodeling is observedare often associated with qualitative and quantitativealterations in PG expression.

STRUCTURE OF GAGs

Glycosaminoglycans are linear carbohydrate chainscomposed of repeating disaccharide units of a hex-osamine (either D-glucosamine or D-galactosamine) andhexuronic acid (either D-glucuronic acid or L-iduronicacid) and are classified as chondroitin sulfate (CS),dermatan sulfate (DS), heparin/heparan sulfate (HS),or keratan sulfate (19) (Table 1). Subsequent O- orN-sulfation (the latter specific to heparin and HS GAGchains), deacetylation, and epimerization of the disac-charide units occur on a subset of sugar residues, whichcan result in an immense diversity in GAG structure (27).Dermatan sulfate is a form of CS in which varying quan-tities of glucuronic acid have been epimerized to iduronic

acid during transport to the cell surface (27,28). Basedon these structural modifications, it has been estimatedthat up to 48 different disaccharide units can occur inany given HS GAG chain, although currently only 23 havebeen detected in vivo (29). By virtue of their sulfate andcarboxyl groups, GAG chains are endowed with a high netnegative charge that contributes to their biological prop-erties and interactions with cytokines, chemokines,growth factors, proteases, and cell adhesion molecules.Chains of GAG rarely occur as free entities but form cova-lent complexes with specific protein cores. In this re-spect, CS and HS GAG chains are covalently attached attheir reducing end to their protein core by an O-glyco-sidic linkage to a serine residue (Figure 1), while keratansulfate is attached through either an O- or an N-glyco-sidic linkage to serine or asparagine respectively. Sincekeratan sulfate has limited distribution, being foundpredominantly in skeletal tissue and not in the perito-neum, the role of keratan sulfate in disease will not bediscussed in this review.

BIOSYNTHESIS OF PGs

Proteoglycan metabolism is a highly regulated anddynamic process, and under homeostasis is under steadystate. Synthesis of PG is initiated by synthesis of the coreprotein, which occurs in the rough endoplasmic reticu-lum and follows the biosynthetic pathway common toall proteins. The protein core is then transferred to theGolgi apparatus where synthesis of a tetrasaccharidelinkage region occurs, initiated by the addition of xy-lose to a serine residue on the core protein, followed bythe addition of two galactose residues, and completedby the addition of glucuronic acid, with each reactionbeing catalyzed by specif ic glycosyltransferases(27,30,31). The class of the GAG chain synthesized onthe linkage region is determined by the glycosylated pro-tein core. The carbohydrate backbone is created by thealternate transfer of N-acetyl-hexosamine and hexuronicacid units from UDP-sugars, transferred sequentially tothe nonreducing end of the growing chain to form ei-ther α- or β-glycosidic bonds with the release of UDP(32). Sulfate esters from 3’-phosphoadenosine 5’-phos-phosulfate are added to the polysaccharide chain bysulfotransferases, which can subsequently be subjectedto further modifications (33). Once the process of GAGchain elongation commences, the process is rapid andPG biosynthesis can be completed within a matter of min-utes. The mature PGs are subsequently packaged invesicles and translocated from the trans Golgi to theirfinal location, whether it is the cell surface, basementmembrane, or ECM.

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CATABOLISM OF PGs

The chemical nature of PGs renders them susceptible todegradation by both enzymatic and non-enzymatic agents.Core proteins may serve as substrate for an extensive arrayof proteases, while GAG chains are subject to degradationby specific sulfatase and glycosidase enzymes. Both thecore protein and the GAG chain are sensitive to cleavagefrom reactive oxygen species and nitric oxide (34,35).Such agents may initiate the catabolism of PGs under bothphysiological and pathological conditions. During normalgrowth and development, degradation of PGs is undermeticulous control, followed by the reabsorption of car-tilage and replacement by bone during endochondral os-sif ication. Increased PG degradation represents anuncontrolled and important aspect of disease pathologyin disorders such as arthritis, tumor invasion, and me-tastasis (36–40). Degradation of PGs in the extracellularmilieu is normally initiated by proteases (cathepsins, ma-trix metalloproteinases, and plasmin) that cleave the coreprotein (40–42). In inflammatory disorders, reactive oxy-gen species are generated by polymorphonuclear leuko-cytes and macrophages, which can cleave both the proteincore and the GAG chain within tissues (43,44).

Perlecan is the most characterized basement membranePG, with a core protein of molecular weight (MW) 400 –470 kDa. It has been suggested that HS PGs of lower MW inbasement membranes may represent proteolytic fragmentsof perlecan (45). In vitro studies have shown that perlecancan be cleaved by matrix metalloproteinase and plasmin(46). The degradation of perlecan in vivo has been associ-ated with pathological disorders such as diabetic nephrop-athy and tumor metastasis (47), and proteolytic fragmentsof the protein core of perlecan have been observed in theurine of patients with end-stage renal failure (48). Thedegradation of HS GAG chains by reactive oxygen specieshas also been described in an animal model of nephriticsyndrome, which subsequently leads to defective glomer-ular filtration and onset of proteinuria (49).

Decorin and biglycan are DS PGs belonging to a fam-ily of small leucine-rich proteoglycans (SLRP). Evidencesuggests that biglycan but not decorin undergoes pro-teolytic processing in normal tissue, with proteolyticcleavage occurring at the amino terminal region of thecore protein. Furthermore, studies have demonstratedthat the abundance of proteolytically modified forms ofbiglycan increase with age in articular cartilage and in-tervertebral discs (50,51). Such proteolytic modifica-tions result in the generation of fragments of biglycancore proteins that are devoid of GAG chains. The func-tional property of fragmented biglycan core proteinslacking the carbohydrate moiety remains to be fully elu-cidated. While limited degradation of decorin is observedin normal cartilage, extensive degradation within theleucine-rich repeat region of decorin is observed in car-tilage from patients with arthritis (52).

ROLE OF HS PGs IN PHYSIOLOGICAL AND PATHOLOGICALCONDITIONS

Heparin/heparan sulfate PGs are ubiquitous macro-molecules found in most mammalian cells and tissues.They have been credited with numerous functions, in-cluding the organization of the ECM through their abil-ity to mediate cell adhesion and migration, cellularproliferation and differentiation, and growth factor

TABLE 1Composition of Glycosaminoglycans

Glycosaminoglycan Repeating disaccharide

Chondroitin sulfate D-glucuronic acid and N-acetylgalactosamineDermatan sulfate D-glucuronic acid/L-iduronic acid and N-acetylgalactosamineHeparan/heparin sulfate D-glucuronic acid/L-iduronic acid and D-glucosamineKeratan sulfate D-galactose and N-acetylglucosamine

Figure 1 — Linkage of glycosaminoglycan chains to their coreprotein. Heparan sulfate, chondroitin sulfate, and dermatansulfate are covalently attached to their core protein via anO-glycosidic tetrasaccharide (xylose–galactose–galactose–glucuronic acid) linkage to a serine residue on the core pro-tein. Xyl = xylose; Gal = galactose; GlcA = glucuronic acid;NAGluc = N-acetylglucosamine; NAGal = N-acetylgalactos-amine; IdoA = iduronic acid.

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sequestration (53–58). They also play an important rolein cell signaling since HS GAG chains act as abundant low-affinity receptors for fibroblast growth factor (FGF), vas-cular endothelial growth factor (VEGF), hepatocytegrowth factor (HGF), and integrins by drawing the ligandonto the cell surface prior to their transfer to a secondhigh-affinity receptor that allows the cell to elicit theappropriate signal (57,59–61). Through their interactionwith HS chains, growth factors have also been shown tobe more resistant to proteolysis and thermal denatur-ation. In this respect, the activity of VEGF damaged byexposure to free radicals can be restored by its interac-tions with HS (62). Interactions between HS and FGF pro-tect FGF from denaturation and proteolytic degradation,thus maintaining a cell surface or matrix-bound reser-voir of FGF for the cells (62).

The importance of HS in development has beenunderscored by studies using targeted disruption of en-zymes responsible for HS synthesis or HS chain modifi-cation, giving rise to severe phenotypes that includedeath at gastrulation through inability to form the me-soderm and extraembryonic tissues, defects in eye, skull,and skeleton formation, perinatal lung failure, and renalagenesis (63–65).

Heparin/heparan sulfate is synthesized on core pro-teins associated with either the cell surface (syndecanand glypican families) or the ECM (perlecan, agrin, andcollagen XVIII). Two or three HS GAG chains are oftenfound in close proximity along the protein core, suggest-ing that they act in a concerted manner in the control ofcell behavior.

Syndecan: Members of the syndecan family are type Itransmembrane PGs comprising four closely relatedmembers (syndecans-1, -2, -3, and -4) encoded by fourdifferent genes (25). The core protein of syndecan rangesfrom 20 to 45 kDa and normally possesses HS GAG chains,although syndecans-1 and -3 have also been shown tocontain CS chains. Syndecan expression shows tempo-ral and spatial specificity and all nucleated cells expressat least one member of the syndecan family. By virtue oftheir ability to bind to numerous extracellular adhesionmolecules (VEGF, fibronectin, collagen, thrombospon-din-1) via their HS GAG chain, syndecans play an essen-tial role in cell–cell and cell–matrix interactions and cellmigration, proliferation, and differentiation (20). Un-like knockout mice for HS synthesis, syndecan-1, -3, and-4–null mice are viable and fertile, with no apparentgross abnormalities. However, post-natal irregularitiesare observed in their response to injury that include in-creased leukocyte–endothelial cell interactions, in-creased angiogenesis, and exaggerated matr ixremodeling (66–68). Changes in expression of syndecan

are often associated with tissue injury or inflammation.Syndecan-1 is the predominant cell surface HS PG iden-tified in epithelial cells where it is required for the main-tenance of epithelial morphology, organization, andbehavior. Loss of cell surface syndecan-1 has been asso-ciated with epithelial-to-mesenchymal transdifferentia-tion (EMT) and is associated with altered cell polarity andcell–cell adhesion (69).

Ectodomain shedding is a proteolytic mechanism bywhich the extracellular domains of cell surface proteinsare released as soluble ectodomains. Approximately 2%of cell surface proteins are thought to be secreted intothe extracellular milieu by this mechanism. Ectodomainshedding is an essential regulatory mechanism of cellu-lar function since it rapidly changes the surface pheno-type of cells and generates soluble biologically activemolecules that can function as either paracrine orautocrine effectors during inflammation, tissue injury,and bacterial infection. In an animal model of lung in-fection, shedding of syndecan-1 ectodomains can be ini-tiated by Pseudomonas aeruginosa to enhance itsvirulence (70). Similarly, Staphylococcus aureus andStreptococcus pneumoniae have been shown to activatesyndecan-1 ectodomain shedding via α- and β-toxinsand zinc metalloproteinases respectively (71,72). Thephysiological function of syndecan-1 shedding remainsto be fully elucidated, but it is possible that ectodomainshedding is a mechanism used by microbes to dysregulatethe host’s response to infection, thereby promoting theirown pathogenesis.

Perlecan: Heparin/heparan sulfate PGs play essentialroles in the structural integrity of basement membranes,interacting with other matrix components to form astable scaffold (47). Due to their ability to attract watermolecules from their surrounding area, they maintainbasement membranes in a hydrated state, which is es-sential for their permselectivity role. Their presence inbasement membranes also allows them to regulate leu-kocyte migration through their ability to sequesterchemokines and provide adhesion ligands, such asL-selectin and P-selectin, for migrating leukocytes (29).

Perlecan is a large multidomain ECM PG that has beenevolutionarily conserved in nematodes, fruit flies, andmammals. The protein core is one of the largest polypep-tides found in vertebrates, with a MW of approximately470 kDa and consisting of five domains that share ho-mology with growth factors and molecules implicated innutrient metabolism, lipid metabolism, and cell prolif-eration and adhesion (54). The core protein has numer-ous sites for O-linked glycosylation, and four potentialsites for HS or CS attachment can be found on domains Iand V. Perlecan is expressed in all basement membranes

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but can also be associated with the cell surface of epi-thelial and endothelial cells through its interaction withintegrins; it is also expressed in connective tissue stro-mata and mesenchymal organs. By virtue of its perva-sive expression and the diversity of its domains, it istherefore not surprising that altered perlecan expres-sion is implicated in a number of pathological disorders,including diabetic complications, cancer, angiogenesis,and atherosclerosis.

The glomerulus contains two ECMs, namely the glo-merular basement membrane (GBM) and the mesangialmatrix. Both contain abundant PGs, such as perlecan,as well as collagens, laminin, fibronectin, and osteo-pontin synthesized by glomerular epithelial cells, endo-thelial cells, and mesangial cells (73,74). Proteoglycanswithin the GBM and mesangial matrix are responsible formaintaining a fixed electronegative charge that restrictsthe passage of albumin and other proteins out of thecapillaries into the urinary space. Furthermore, thesePGs provide structural support and the ability to seques-trate cytokines and growth factors essential for prolif-eration and matrix synthesis. In pathological disorderssuch as diabetic nephropathy, the GBM is thickened withelevated collagen type IV expression and a concomitantdecrease in overall HS PG content, the latter consequentto transcriptional and posttranscriptional modifications.Recent studies have demonstrated that a decrease inN-sulfation of HS GAG chains occurs in the diabetic kid-ney, suggestive of a decrease in anionic charge in theGBM (75). The importance of HS chains in the mainte-nance of glomerular filtration is highlighted in animalstudies in which treatment of rat kidneys in vivo withheparitinase resulted in an increased urinary secretionof both ferritin and albumin (76). Altered sulfation pat-terns in HS PGs are not restricted to the GBM since HSextracted from diabetic livers also has reduced sulfationlevels (77,78). Furthermore, animal and clinical studieshave demonstrated an inverse correlation between HSPG expression in the GBM and proteinuria (79–81). Incontrast to this is the notion that loss of HS PGs is notcrucial for the development of proteinuria since alter-native rescue pathways and compensatory mechanismscan be used by the kidney (54).

Studies have shown that cancer metastasis requiresthe depletion of basement membrane HS, which wouldfacilitate the migration of cancerous cells to differentsites (82,83). However, HS PGs are also required to in-fluence cell proliferation. Perlecan occupies a strategicposition in basement membranes, which allows the mac-romolecule to bind growth factors, thereby modulatingtheir biological activity (84). Most tumor cells identifiedin breast, liver, colon, and melanoma have increased

perlecan expression to enhance their responses togrowth factors such as FGF and TGF-β1, and such inter-actions are, in part, responsible for inducing tumor an-giogenesis (85–86).

Genetic defects in perlecan expression result in dete-rioration of basement membranes in regions of increasedmechanism stress, as observed in Hspg2–/– mice. Thesemice develop defects in the basement membrane thatseparates the brain from the adjacent mesenchyme, re-sulting in the invasion of brain tissue into the overlay-ing ectoderm, causing lethality and severe cephalicabnormalities. Perlecan deficiency also results in base-ment membrane deterioration of the myocardium, re-sulting in blood leakage into the pericardium and cardiacarrest (87,88). Cartilage abnormalities are also observedin perlecan-null mice and those embryos that survive tobirth have reduced chondrocytic proliferation in thegrowth plate, resulting in dwarfism. These morphologi-cal abnormalities are also observed in lethal dysseg-mental dysplasia, Silver-Handmaker type (DDSH), asevere form of human dwarfism. Studies have demon-strated that duplication of exon 34, frame shifts, andpoint mutations result in the generation of truncatedforms of perlecan core protein in DDSH patients (54).These fragments are apparently unstable and undergodegradation since small amounts of perlecan are ob-served in the cartilage of these patients. Destabilizationof basement membranes and growth factor signaling istherefore prevalent in disorders in which perlecan syn-thesis is altered.

Other diseases that are influenced by HS PGs includeatherosclerosis, in which HS has been demonstrated tocontrol smooth muscle cell proliferation, cells respon-sible for the increased synthesis of matrix components.Proliferation of smooth muscle cells is regulated byperlecan through the activation of PTEN, a tumor sup-pressor gene, which acts to decrease the activity of focaladhesion kinase via the ERK pathway (89).

ROLE OF DECORIN AND BIGLYCAN IN PHYSIOLOGICAL ANDPATHOLOGICAL CONDITIONS

While the roles of HS PGs in physiologic and patho-logic conditions have been extensively studied, fewerstudies have been appropriated to the CS/DS PGs.Decorin and biglycan are members of the SLRP familydistributed throughout most connective tissues (90).Decorin and biglycan possess a core protein of MW ap-proximately 45 kDa that carries one and two CS/DS GAGchains respectively. The structurally related core proteinscomprise 12 consecutive repeats of 24 amino acid resi-dues with numerous leucine residues in conserved

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positions. While decorin and biglycan share homologyin their protein and carbohydrate structure, their expres-sion and localization are considerably distinct. Decorinis identified in the ECM, while biglycan is associated withthe cell surface and pericellular environment. In thenormal kidney, distinct and spatially different expres-sions of decorin and biglycan have been observed, suchthat decorin is synthesized by mesangial and interstitialcells, while biglycan is expressed by all cells present inthe glomerulus, Bowman’s capsule, and interstitium (91).

Decorin is composed of three domains comprising anN-terminal region where attachment for a single-chainDS chain is found, a central region composed of 10 leu-cine-rich repeats that are the principal sites of interac-tion with other proteins, and a cysteine-rich C-terminalregion. Decorin can interact, through either its core pro-tein or DS GAG chain, with numerous matrix componentsthat include collagen types I, II, III, VI, XII, and XIV,fibronectin, thrombospondin-1, and tenascin-X. To-gether with its ability to induce matrix metalloproteinaseexpression, this is suggestive that decorin plays a criti-cal role in matrix assembly and turnover. The role ofdecorin in the assembly of collagen fibrils, essential forthe framework of any tissue, has been extensively stud-ied (92–95). Decorin acts as a bridge securing two par-allel collagen chains together, endowing the resultantcollagen with stability and increased tensile strength.Furthermore, decorin can regulate fibril diameter dur-ing its formation and limit access of collagenases to theircleavage sites on collagen molecules, protecting col-lagen molecules from proteolytic injury (96). The essen-tial role of decorin in collagen f ibrillogenesis, inparticular in the skin and tendons, has been underscoredin studies employing the decorin knockout mouse,whereby mice lacking decorin have lax and fragile skin,with dermal thinning and loose connective tissue in thedermal and hypodermal layers of the skin (94,97). Com-pared to the wild-type mice, decorin-null mice exhibitcollagen fibrils of highly irregular diameter and abnor-mal fibrillar organization consequent to uncontrolledlateral fusion of thick and thin fibrils. In the absence ofdecorin, reduced tensile strength compromises the heal-ing process of the skin (97). Decorin has been shown toregulate the cell cycle, and its secretion in cells underphysiologic conditions can suppress cell proliferation;in pathologic conditions, decorin has been shown to in-hibit tumor cell-induced angiogenesis (94) and modu-late macrophage activation (98). Decorin-null mice havean increased density of periodontal fibroblasts, possi-bly a result of abrogation of the growth inhibitory activ-ity or the negative feedback regulatory mechanism ofdecorin.

In addition to its critical role in collagen fibrillo-genesis, decorin is able to influence matrix synthesis byits ability to sequester growth factors. While HS PGs bindand sequester growth factors through their HS GAGchain, decorin binds growth factors through its core pro-tein. Studies by independent researchers have shownconvincingly that decorin acts as an important modula-tor of TGF-β1 bioavailability, whereby the core proteinof decorin binds to TGF-β1 and, in doing so, neutralizesthe biological activity of TGF-β1, thus preventing theprofibrotic peptide from binding to its cell surface re-ceptor (22,99–102). The decorin–TGF-β1 complex gen-erated is deposited in the ECM, where it acts as a reservoirfor TGF-β1, and is presented back to the cells when cellsrequire the growth factor (Figure 2). The interactionbetween decorin and profibrotic mediators would haveimportant implications in the prevention of tissue fibro-sis, but studies have shown it to be cell, tissue, and spe-cies specific (103). The importance of decorin in theprogression of fibrosis is underscored by a study under-taken by Schaefer et al., who demonstrated that the de-velopment of tubulointerstitial fibrosis in an animalmodel of obstructive nephropathy was more prominent

Figure 2 — Modulation of transforming growth factor beta-1(TGF-β1) bioactivity by decorin in the peritoneum. Decorin canbind TGF-β1 via its core protein. In doing so, decorin will neu-tralize the activity of TGF-β1 and prevent it from binding to itscell surface receptors. The decorin–TGF-β1 complex is depos-ited in the extracellular matrix (ECM), where it acts as a reser-voir for TGF-β1. This interaction can be dissociated and TGF-β1presented to mesothelial cells when the peptide is requiredfor maintenance of peritoneal homeostasis or during woundhealing. DS = dermatan sulfate; GAG = glycosaminoglycan.Modified from Border et al. Ref. (99).

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in decorin-null mice than in the wild-type mice charac-terized by enhanced collagen type I degradation, renalatrophy, and increased apoptosis (104). In experimen-tal mesangial proliferative glomerulonephritis, systemicadministration of decorin to the animals, or decorin genetherapy, has been shown to abrogate ECM accumulationwithin the kidney and to improve proteinuria (22,105).

Decorin also plays a role in organogenesis and tissuedifferentiation since it is expressed in all organ-lininglayers, including the pericardial, pleural, and peritonealmesothelium, and parenchymal capsules, suggestive ofa role for decorin in organ shaping and in epithelial-to-mesenchymal interactions during organ development(106).

Biglycan was first identified as a major PG of bone.Its structure is similar to that of decorin except that itcontains two rather than one DS GAG chain. It is highlyexpressed in the extracellular matrices of bone and car-tilage and is localized at the cell surface. Targeted dis-ruption of the biglycan gene results in abnormal collagenfibril morphology and in a phenotype typical of osteo-porosis, whereby biglycan-null mice develop reducedgrowth rates and decreased bone mass consequent tomultiple defects in bone marrow stromal cells (107).

Despite its abundance in different tissues, the pre-cise role of biglycan remains to be fully elucidated. Whilebiglycan has been demonstrated to interact with TGF-β1,whether it can neutralize the biological effect of TGF-β1remains a discussion for debate. Unlike decorin, biglycandoes not inhibit cell growth, but rather has been shownto stimulate the growth and differentiation of monocyticlineage from various lymphatic organs (108,109).Biglycan expression is increased in atherosclerotic le-sions and it has been suggested to play a role in the regu-lation of vascular smooth muscle growth and migrationthrough cdk2- and p27-dependent pathways. It is pos-sible that changes in biglycan expression may be a fac-tor that influences the susceptibility of arteries tovascular injury (110). In contrast to decorin, over-expression of biglycan has no effect on ameliorating tis-sue fibrosis.

ROLE OF BIKUNIN IN PHYSIOLOGICAL AND PATHOLOGICALCONDITIONS

Inter-α-trypsin inhibitor is an extraordinary PG in thatit contains three protein chains (heavy chain-1, heavychain-2, and 1 light chain, the latter often referred toas bikunin). Bikunin carries a CS GAG moiety to whichthe heavy chains are covalently attached. It is somewhatoverlooked in the field of PGs since it is rarely found inthe ECM, its core protein is highly homologous to serine

protease inhibitors rather than other PGs, and its asso-ciation with the heavy chains often masks the smallCS GAG moiety. The majority of circulating bikunin isfound in the complex form of inter-α-trypsin inhibitoror its pre form, pre-inter-α-trypsin inhibitor. Free circu-lating bikunin accounts for 2% – 10% of the total circu-lating concentration in healthy individuals, while themajority of bikunin in the urine is in its free form whereit acts as the urinary trypsin inhibitor (111,112). Al-though bikunin is expressed in the pancreas, kidney,lungs, and heart, it is primarily synthesized and secretedby the liver and occurs in the circulation and urine asthe predominant CS PG, reaching levels of 30 –100 µg/mL and <5 µg/mL, respectively, in healthy indi-viduals (113). These levels may be elevated >100-fold inpatients with pathological disorders that include renalfailure, rheumatoid arthritis, cancer, or infection (113).The CS moiety of bikunin is short, having a MW of ap-proximately 8 kDa and comprising 12 – 18 disacchariderepeats of glucuronic acid and N-acetylgalactosamine.Under inflammatory conditions, the chain length of theCS GAG may increase by up to eight disaccharide repeatsand may possess a reduced sulfation pattern (114). Theimplication of qualitative changes in CS GAG chains dur-ing inflammation is currently unknown.

Proteases are elevated during inflammatory proces-ses and infection. Bikunin acts as an anti-inflammatorymediator by its ability to inhibit serine proteases, in par-ticular the actions of elastase, which results in the sup-pressed activity of immune cells, inhibition of malignantcell metastasis, and stabilization of the ECM architec-ture (111). The protective role of bikunin in basementmembrane destruction is highlighted during inflamma-tion of the kidney, although this observation is notspecific to renal damage. In glomerulonephritis, poly-morphonuclear leukocytes and macrophages induce cap-illary wall injury, mediated by the release of proteases.These proteases are localized to the glomerular capillarywall whereby they degrade components of the GBM, re-sulting in increased glomerular permeability and pro-teinuria (112). The body’s natural response to aneutrophil invasion is the release of active protease in-hibitors from their pro form. In this respect, elastase andcathepsin G act on inter-α-trypsin inhibitor to releasebikunin, which in turn reduces basement membranedamage.

The role of bikunin in the inflammatory process hasbeen further investigated by Wakahara and colleaguesusing bikunin-null mice after the intraperitoneal admin-istration of lipopolysaccharide. These researchers dem-onstrated that, in the absence of bikunin, mice faredsignificantly worse than their wild-type littermates in

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survival rate, possibly a result of their increased sensi-tivity to enhanced levels of proinflammatory cytokinesin the plasma and also their induction by peritoneal mac-rophages (115).

A role for bikunin in reproductive biology has also beenrecognized (116,117). In the preovulatory follicle, theoocyte is surrounded by compact layers of follicle cells,forming the cumulus cell–oocyte complex (COC). In re-sponse to an increased surge in gonadotropin levels, theCOC in any follicle destined for ovulation undergoes ex-pansion once an extensive hyaluronan-rich ECM is syn-thesized around and between the cumulus cells.Successful expansion of the COC appears to be essentialfor ovulation and ultimately for fertilization (116,118).The hyaluronan-rich matrix surrounding the COC isformed by the covalent interactions of hyaluronan withthe heavy chains of inter-α-trypsin inhibitor. The gen-eration of inter-α-trypsin inhibitor is dependent on thesynthesis of bikunin. Female bikunin-null mice thereforeexhibit severe infertility consequent to their inability todevelop a hyaluronan-rich cumulus oophorus around theoocytes (113,118). Such findings highlighted a pivotalrole of bikunin in the activation, transportation, andpresentation of the heavy chains to newly synthesizedhyaluronan in the expanding cumulus oophorus.

PUTATIVE ROLES OF PGs/GAGs IN PERITONEAL HOMEOSTASISAND PATHOLOGY

The presence of anionic sites within the peritonealmicrovasculature, subserosal interstitium, and basallamina suggests that, far from being a passive mem-brane, the peritoneum is a negatively charged dialyzingmembrane that mediates transperitoneal protein trans-port (10). This conception was underscored by Gotloibet al., who demonstrated in a murine model of acute sep-tic peritonitis that a reduction in the density of anionicsites along the submesothelium was associated with in-creased microvascular and mesothelial permeability tonegatively charged plasma proteins (12). Renvall dem-onstrated that peritoneal resident cells were capable ofsynthesizing both glycoproteins and PGs, the synthesisof the latter contributing to the anionic sites previouslyidentified in the peritoneal membrane (119). Further-more, these PGs and GAGs may contribute to the anioniccharge distribution in the glycocalyx surrounding theapical aspect of the mesothelium, acting as a lubricantand protecting the peritoneal mesothelium from surfacefriction and adhesion formation.

In Vitro and In Vivo Synthesis of PGs/GAGs by HPMCs:In vitro, HPMCs synthesize a number of PGs that may con-tribute to the negative charge of the peritoneal mem-

brane. Under basal conditions, HPMCs were shown tosynthesize predominantly decorin and biglycan, whichaccounted for 52.5% of their total de novo synthesizedPGs (15). Since they are secretory PGs, they are also de-tected in spent dialysate obtained from PD patients (15).The major HS PGs synthesized by HPMCs are syndecan-1and perlecan, which comprise 17% and 5% respectivelyof the total PGs. Perlecan was identified predominantlyin the ECM compartment while syndecan-1 was foundwithin the mesothelial cell layer and in a secreted form.Prolonged exposure of cultured HPMCs to elevated glu-cose concentrations simulating PD resulted in a dose-dependent decrease in the de novo synthesis of perlecancore protein and its HS GAG chains, although the lengthand charge of the GAG chain remained unaltered (5).These effects were mediated in part through elevatedglucose induction of TGF-β1. In contrast to mesangialcells and fibroblasts, which are known to synthesizeperlecan polypeptides with a high MW (250 – 300 kDaand 400 – 470 kDa respectively), perlecan core proteinsynthesized by HPMCs possessed a MW of approximately173 kDa under both basal and stimulated conditions. Thisreduction was not a consequence of proteolytic degra-dation or a result of internal degradation. Size variantsof perlecan may be a result of alternative splicing, asdemonstrated in the Engel–Holm–Swarm tumor matrix.

Analysis of peritoneal biopsies showed that, whileperlecan expression was prominent in the mesotheliumof peritoneal specimens obtained from patients com-mencing PD, it was significantly reduced in the mesothe-lium but increased in the submesothelium of samplesobtained from established PD patients (5). Mean me-sothelial perlecan expression inversely correlated withsubmesothelial thickening, which was in accordance withthe observation from Shostak et al., who demonstratedthat reduced charge density in the rat mesothelium dur-ing experimental PD was accompanied by increased peri-toneal permeability to plasma proteins (120). Theobservation that thickening of the submesothelium wasassociated with increased perlecan expression in thesame compartment (5) would suggest that perlecan isinvolved not only in peritoneal homeostasis and perito-neal permeability but also in peritoneal fibrosis. Alteredsynthesis of PGs during PD would therefore have poten-tially serious implications in peritoneal transport of pro-teins, host defense, wound healing, inflammation, andfibrosis.

Bikunin was identif ied in spent dialysate and ac-counted for approximately 65% of the total identifiedCS GAGs/PGs in PD fluid, of which 43% was present in itsfree form with a MW of approximately 50 kDa (121). Aquestion arose as to the origin of bikunin. While not de-

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tected in normal human serum, bikunin was present inserum samples obtained from patients receiving PD andin individuals with elevated levels of creatinine, indica-tive of renal failure but yet to receive renal replacementtherapy. The detection of free bikunin in serum samplesobtained from these patients is probably related to lossof renal function. Therefore, one can propose that leak-age of bikunin from the circulation contributed to thelevels found in PD fluids (121).

Role of PGs/GAGs in Pericellular Coat Formation in thePeritoneum: Various cell types that include mesothelialcells are surrounded in vitro by a pericellular matrix, orcoat, which can be easily visualized by its ability to ex-clude erythrocytes. Pericellular coats play critical rolesin the stabilization of the cellular microenvironment andthe ECM, as well as in differentiation and protection ofcells from viral attack and from the cytotoxic effects oflymphocytes. Pericellular coats are synthesized by theinteractions of hyaluronan and inter-α-trypsin inhibi-tor, akin to that observed in the COC prior to ovulation.While hyaluronan has been identified in the pericellularcoats of mesothelial cells, its full composition remainsto be fully identified. Hyaluronan is found in elevatedquantities in spent dialysate from noninfected PD pa-tients, the titers of which are exacerbated in spent PDfluids from patients with peritonitis (122). It is thus pos-sible that peritoneal hyaluronan interacts with inter-α-trypsin inhibitor to generate a pericellular coat orglycocalyx around HPMCs, and in doing so releases freebikunin and CS GAG into the peritoneal cavity. The physi-ological role of hyaluronan and inter-α-trypsin inhibi-tor complex in the per itoneum may be to protecthyaluronan against fragmentation by reactive oxygenspecies, especially during peritoneal inflammation.

Role of PGs/GAGs in Peritoneal Inflammation: The ob-servation that decorin and biglycan are the major PGssynthesized by HPMCs raises the question of their func-tional importance in the physiology and pathology of theperitoneum. In the setting of peritoneal homeostasis,decorin may contribute to the stability of the ECM,growth regulation, cell proliferation, inflammation, andanticoagulation through its interaction with matrix com-ponents, growth factors, chemokines, and thrombin,respectively (Table 2). During chronic PD, decorin syn-thesis and secretion is increased in HPMCs (Yung S andChan TM, manuscript in preparation), and such an in-duction may represent the cells’ adaptation to perito-neal host defense, fibrosis, and angiogenesis. Chronicperitoneal inflammation is commonly observed in estab-lished PD patients and is exacerbated during episodesof peritonitis. An essential component of any inflamma-tory response is the rapid recruitment of leukocytes from

the bloodstream to the site of the inflammation throughpostcapillary venules. Key events in leukocyte recruit-ment include the initial attachment and rolling of leu-kocytes on the inflamed endothelium, activation of theleukocytes by chemokines attached to endothelial cells,stable adherence to the endothelium of the activatedleukocytes, degradation of the subendothelial basementmembrane, and migration of the leukocytes via a chemo-tactic gradient into the injured tissue, where they influ-ence immune activities and participate in tissue repair(29). Analogous to the functional role of endothelial cellsin leukocyte extravasation, HPMCs control leukocyte traf-ficking and their admission into the peritoneal cavitythrough the creation of a chemotactic gradient acrossthe mesothelium.

Chemokines are a family of small peptides that can beclassified as constitutive chemokines that are homeo-static ligands responsible for routine immune surveil-lance, leukocyte traf f icking, and developmentalprocesses, or as inducible chemokines that are expressedconsequent to physiological stress and inflammation.They interact with seven transmembrane G protein-coupled receptors on leukocytes, triggering changes inadhesive interactions with the ECM and cell surfaces tomediate locomotion (29). In addition to their interac-tion with the high-affinity G protein-coupled receptors,chemokines can bind to the GAG moiety of PGs on theendothelial surface, which acts as a mechanism for cellsurface retention and possibly for their presentation tocirculating leukocytes (27,123,124). In the absence ofsuch a mechanism, chemokine gradients would be eas-ily disturbed by diffusion. The interaction of chemokineswith GAG chains is specific and may result in an alterna-tive pathway in the control of cell migration, in the acti-vation of specific signal transduction processes that areindependent of chemokine G protein-coupled receptorinteractions, and in the prevention of chemokine pro-teolysis. Such complexes may also serve as a reservoirfor chemokines necessary for rapid mobilization with-out the induction of de novo protein synthesis.

Cultured HPMCs synthesize monocyte chemoattrac-tant protein-1, RANTES, and interleukin (IL)-8 in re-sponse to proinflammatory cytokine stimulation (125).These chemokines have been shown to bind to DS with ahigh iduronic acid content, although the affinity for DSvaries depending on the individual chemokine (126).Soluble GAG chains have been shown to reduce inflam-mation possibly through their ability to block chemokine-mediated leukocyte activation, as observed in numerousanimal models of inflammation, including adjuvantarthritis and thioglycollate-elicited neutrophil accumu-lation (124). Since decorin and biglycan secreted by

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HPMCs possess GAG chains that contain approximately90% iduronic acid residues, it is likely that they play apivotal role in reducing peritoneal inflammation.

Syndecan-1 may also play a pivotal role in the gen-eration of chemokine gradients within the peritonealcavity and mediation of lymphocyte infiltration duringinflammation. Heparin/heparan sulfate GAG chains, pos-sibly those of syndecan-1, have been demonstrated toactivate peritoneal macrophages, resulting in inducedsynthesis of intercellular adhesion molecule-1 and in-creased secretion of IL-6, IL-1β, tumor necrosis factor-alpha, TGF-β1, and prostaglandin E2 (127). Whileperitoneal inflammation, peritonitis, and tissue injuryare associated with altered synthesis of PGs andchemokines, how such changes modify the GAG–chemo-kine interactions and the formation of a chemotacticgradient remains to be fully elucidated.

Role of PGs/GAGs in Peritoneal Neoangiogenesis andFibrosis: Angiogenesis, the formation of new capillariesfrom preexisting vessels, is critical in physiologicalevents such as embryonic development and wound heal-ing, and in pathological processes that include healing,rheumatoid arthritis, tumor growth and metastasis, anddiabetic retinopathy. Recent studies have demonstratedthat decorin is increased in endothelial cells of capillaryneovessels in areas that contain large quantities of mac-rophages, suggestive that decorin may play a key role inangiogenesis in vivo, in particular when angiogenesis isinduced by inflammation (128). The constant exposureof the peritoneum to unphysiological PD fluids resultsin neoangiogenesis (1,129). While it is unclear whetherperitoneal endothelial cells can synthesize decorin,given that endothelial cells of the glomerulus, cornea,microvessels, and umbilical cord are capable of synthe-

sizing decorin, it is most probable that peritoneal endo-thelial cells too can synthesize decorin, thus providinga potential role of decorin in the regulation of perito-neal neoangiogenesis. It is also possible that decorinsecreted into the peritoneal cavity by HPMCs may play aregulatory role in the formation of new blood vessels,but further studies are warranted to confirm this.

The functional role of decorin in inflammation-asso-ciated angiogenesis remains to be fully elucidated but,based on the current knowledge of the functional prop-erties of decorin, several possible mechanisms can beproposed. Since decorin can interact with componentsof the ECM, through its ability to influence the organi-zation of these molecules and ECM assembly, decorin mayprovide endothelial cells with a substrate by which newcapillary tubes are produced. Decorin may also regulateangiogenesis through its ability to regulate the activityof proangiogenic and antiangiogenic growth factors suchas FGF and TGF-β1 respectively. With respect to the lat-ter peptide, by its ability to sequester TGF-β1, decorinmay also play a pivotal role in regulating peritoneal ma-trix synthesis. Its increased synthesis in HPMCs afterexposure to PD fluids may be a reflection of its ability tocontrol peritoneal fibrosis. In an animal model of PD,Margetts et al. demonstrated that the incorporation ofadenovirus-mediated gene transfer of decorin into theseanimals reduced peritoneal fibrosis, although decorinhas no effect on peritoneal vasculature or peritonealfunction (130).

Role of PGs/GAGs in EMT and Remesothelialization: Cellsurface HS PGs are often substantially more abundantthan most receptors and modulate the interactions ofextracellular protein ligands with their receptorsthrough the formation of HS–protein complexes, and in

TABLE 2Binding Interactions of Dermatan Sulfate Proteoglycans — Potential Role in the Peritoneum

Binding protein Effect on the peritoneum

Collagen Stability of ECM architectureFibronectin Stability of ECM architecture; proliferationTenascin-X Stability of collagen matrix; maintenance of peritoneal basement membrane tensile strengthRANTES Modulation of chemotactic gradient; inflammatory responseIFN-γ Facilitation of binding of ligand to cell surface receptor; induction of nitric oxide generationTGF-β1 Limitation of bioavailability of profibrotic peptide; reduction of peritoneal fibrosis; regulation of growthFGF-2 Proliferation of cells through tyrosine kinase activation; wound healingHGF Proliferation of cells; regeneration of cells; differentiation, migration, angiogenesisLDL AtherosclerosisThrombin AnticoagulationHeparin cofactor II Inactivation of thrombin

INF-γ = interferon gamma; TGF-β1 = transforming growth factor beta-1; FGF-2 = fibroblast growth factor-2; HGF = hepatocytegrowth factor; LDL = low density lipoprotein; ECM = extracellular matrix.

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this manner modify the actions of growth factors,cytokines, proteases, adhesion molecules, and ECM com-ponents. Syndecan-1 was identified on the cell surfaceof HPMCs and also in the soluble form. Its role in the peri-toneum is currently unknown but, given that it can bindto FGF, it is possible that syndecan-1 can influence cellmigration and proliferation and tissue injury. Constantexposure of mesothelial cells to PD fluids leads to thedenudation of the mesothelium. Since syndecan-1 isoften associated with cells at the leading edge of awound, it is possible that syndecan-1 plays a role in theremesothelization of the monolayer after chemical (el-evated glucose concentrations, lactate) or bacterial(peritonitis) insult. Transformation of cells to a mesen-chymal phenotype in various carcinomas is associatedwith loss of syndecan-1. Since EMT is often observed inPD patients, shedding of syndecan-1 into PD fluid may, inpart, contribute to the change in mesothelial phenotype.The shedding of syndecan-1 from the mesothelial cell sur-face may potentially be a regulatory mechanism in sig-naling events and is often accelerated by mediators oftissue injury and microbial infections. Although HS PGshave been identified in spent dialysate (Yung S and DaviesM, unpublished data), its/their identity remain(s) to beclarified, but it is possible that syndecan-1 may contrib-ute. Excessive shedding of syndecan-1 can enhance pro-teolytic activities of neutrophil elastase and cathepsin G,inhibiting cell proliferation during wound healing. Shouldthis occur in the peritoneum during chronic PD or epi-sodes of peritonitis, the rate of remesothelializationwould be reduced and angiogenesis hampered.

Transforming growth factor-β1 has also been demon-strated to induce EMT in HPMCs in vitro (7). Givendecorin’s ability to neutralize the bioavailability ofTGF-β1, perhaps it can act as an antagonist to EMT. Fur-ther studies are warranted to confirm this. It must benoted, however, that while EMT occurs in vitro, this pro-cess remains controversial in vivo and further morpho-histological analyses of the peritoneum are necessaryto corroborate the in vitro data.

Role of PGs in the Permselectivity of the Peritoneal Base-ment Membrane: Perlecan is found mainly in the extra-cellular milieu of cultured HPMCs (5). It is a basementmembrane HS PG found at the periphery of cells. Withinthe peritoneal cavity, perlecan may have distinct biologi-cal functions, including maintenance of the structure andpermselectivity barrier of the peritoneal basement mem-brane. Loss of perlecan in the peritoneal mesotheliumduring chronic PD may result in increased passage ofplasma proteins into the peritoneal cavity. It is of inter-est that charge selectivity of peritoneal protein trans-por t is def icient in established PD patients, but

decreased synthesis of basement membrane PGs may ac-count for this phenomenon (131,132).

THERAPEUTIC STRATEGIES USING GAGs IN THE PRESERVATIONOF THE STRUCTURAL AND FUNCTIONAL INTEGRITY OF THEPERITONEUM

Since its discovery in 1917, heparin has been used ex-tensively in the clinical setting. Natural preparations ofheparin commonly isolated from bovine lung or porcineintestinal mucosa can vary substantially in their repeat-ing disaccharide units and different MWs. As a result, thebiological actions of heparin can differ significantly be-tween different batches of heparin preparations. The ini-tial activity ascribed to heparin was its anticoagulantproperty through its ability to interact with thrombin and,previously, it was very often used in the treatment of pa-tients at risk of, or with established, thromboembolic dis-orders (133). To date, low MW heparins are increasinglyused in the management of these disorders since they areas effective as unfractionated heparins but have theadded advantages of a longer elimination half-life, morepredictable anticoagulant effect, and lower risk ofosteopenia and heparin-induced thrombocytopeniatype II (133).

Heparin is added to PD solutions at a concentrationof 1 IU/mL to prevent fibrin formation. At this concen-tration, in vitro studies have shown no cytotoxic orgrowth inhibitory effects on HPMCs (134). Using thisconcentration, we have also demonstrated that heparincan reduce elevated glucose-mediated alterations inperlecan synthesis in HPMCs (manuscript in prepara-tion). Animal and clinical PD studies have also demon-strated that the intraperitoneal administration ofheparin can improve ultrafiltration, inhibit the forma-tion of thrombin, and prevent peritoneal f ibrosis,thereby improving the structural and functional proper-ties of the peritoneum (135–139).

Chondroitin sulfate has also been demonstrated toimprove ultrafiltration in an animal model of PD throughits ability to reduce glucose absorption (140,141).Breborowicz and colleagues hypothesized that CS maybecome entangled with matrix components in the peri-toneal interstitium, which may subsequently increaseresistance to water flow. Transperitoneal loss of proteinswas also reduced in animals receiving CS (140).

The supplementation of PD solutions with hyaluronan,a non-sulfated GAG, has received much attention overrecent years and has been demonstrated to significantlyimprove the structural and functional properties of theperitoneal membrane. An in-depth review of all articlesrelating to hyaluronan supplementation during PD falls

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outside the scope of this review, but readers are directedto the article written by Diaz-Buxo and Gotloib regard-ing agents that modulate the functional and structuralproperties of the peritoneum (18).

CONCLUSIONS

The field of PGs in inflammatory disorders and dis-ease is one of the most active research areas ofglycobiology to date. Proteoglycans and GAGs have beenshown to influence or control almost all aspects of cel-lular and biological functions. This review has focusedpredominantly on the functions of the PGs and GAGs thathave been identified in the peritoneum, and their puta-tive roles in peritoneal inflammation, angiogenesis, andfibrosis. It is without doubt that, as more PGs are identi-fied in the peritoneum, further biological functionswithin the peritoneal cavity will be bestowed upon them.With increased applications in the field of glycomics, itis with much anticipation that further knowledge intothe complexity of PG synthesis and GAG chain modifica-tion, the roles of individual core protein and GAG chainsin biological functions, and how qualitative and quanti-tative changes influence pathological disorders will allowus to elucidate further the relentless role of PGs and GAGsin physiological and pathological processes.

ACKNOWLEDGMENTS

Part of this work was supported by an RGC grant (HKU7240/98M) and the Wai Hung Charity Foundation.

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