| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Cells and Matrix |
Department of Medicine, University of Hong Kong, Hong Kong SAR, PR China
Correspondence to: S. Yung, Department of Medicine, Room 302, New Clinical Building, Queen Mary Hospital, Pokfulam, Hong Kong SAR, PR China. ssyyung{at}hkucc.hku.hk
 |
ABSTRACT |
|---|
 TOP ABSTRACT DISCUSSIONCONCLUSIONSREFERENCES |
|---|
Background: By virtue of their high net negative
charge, glycosaminoglycans and proteoglycans play pivotal roles in biologic
processes such as cell–cell and cell–matrix interactions,
sequestration of growth factors, activation of chemokines and cytokines, and
permselectivity of basement membranes. Methods: The present article reviews the putative roles
of glycosaminoglycans and proteoglycans in the peritoneal cavity during normal
peritoneal homeostasis and chronic inflammation, the latter induced by
constant exposure of the peritoneum to non-physiologic peritoneal dialysis
(PD) solutions. Results: Glycosaminoglycans have been identified in the
mesothelial glycocalyx, a slippery, non-adhesive layer that protects the
peritoneal membrane from abrasion and infection. Dermatan sulfate
proteoglycans can neutralize the activity of transforming growth factor
β1 and can thus play an essential role in modulating peritoneal fibrosis.
Heparan sulfate proteoglycans play a crucial role in the sequestration of
growth factors; they also modulate selective permeability of proteins across
the peritoneal cavity. Reduced expression of perlecan, a heparan sulfate
proteoglycan of the basement membrane, is observed in peritoneal biopsies
obtained from established PD patients, consequent to prolonged exposure to the
elevated glucose concentrations in conventional PD solutions. Supplementation
of PD fluids with glycosaminoglycans has been shown to be beneficial to both
the structural and functional integrity of the peritoneum. Conclusions: Recent advances in the field of
glycobiology have revealed a multitude of biologic processes that are
controlled or influenced by glycosaminoglycans and proteoglycans. Altered
synthesis of these macromolecules during PD has serious implications for the
peritoneal transport of proteins, host defense, wound healing, inflammation,
and fibrosis.
KEY WORDS: Decorin; perlecan; hyaluronan; mesothelial cells.
Ultrastructure studies using ruthenium red have highlighted the presence of anionic sites on the surface of mesothelial cells and the underlying basal lamina (1). This electronegative charge barrier is believed to modulate transport of proteins across the peritoneal membrane, because loss of anionic charge from either peritonitis or chemical neutralization results in increased peritoneal permeability to plasma proteins (2,3). Currently, only limited data are available on the chemical nature of these anionic sites. Given that glycosaminoglycans (GAGs) have been isolated from spent dialysis effluent (4), GAGs and proteoglycans (PGs) likely account, at least in part, for the ruthenium red staining. The present brief review describes the putative functions of PGs and GAGs in relation to the peritoneum and peritoneal dialysis (PD).
|
DISCUSSION |
|---|
|
TOPABSTRACTDISCUSSIONCONCLUSIONSREFERENCES |
|---|
The four structurally distinct GAG families include hyaluronan, chondroitin or dermatan sulfate, heparan sulfate, and keratan sulfate (Table 1). Although individual PGs exhibit minor changes in the basic carbohydrate backbone of the GAG chain, the subsequent modifications in sulfation pattern, deacetylation, and epimerization of GAG chains are what provide for the specific activities of the PG molecules (7). The exception is hyaluronan, which is neither sulfated nor attached to a core protein.
|
Biosynthesis of PGs begins with the initial biosynthesis of the core protein in the rough endoplasmic reticulum and follows the mechanism seen with other proteins. The core protein is transported to the Golgi apparatus, where addition of GAG chains occurs (8). The PGs are classified according to their protein core, their structure, and their functions (Table 2).
|
THE PUTATIVE ROLES OF PGs IN THE PERITONEUM
The structural diversity of the PGs underlie their numerous functions,
which range from mechanical functions essential for maintenance of tissue
architecture to critical roles in cell proliferation, cell adhesion,
inflammation, wound healing, and fibrosis.
PGs and the Mesothelial Glycocalyx: The surface of the mesothelium is surrounded by a glycocalyx composed of GAGs, PGs, and phospholipids, which together provide a slippery, non-adhesive layer that protects the serosal cavity from abrasion, infection, and tumor dissemination (10). The GAG and PG composition of the mesothelial glycocalyx remains to be fully defined. Similarly, whether these macromolecules are synthesized by resident peritoneal cells or are transported through the mesothelium is currently uncertain.
Human peritoneal mesothelial cells (HPMCs) synthesize and secrete decorin, biglycan, perlecan, and hyaluronan in vitro (11–15). That finding, together with the observation that hyaluronan, decorin, and biglycan have been identified in spent dialysis effluent, lends support to the suggestion that HPMCs contribute to the anionic content of the mesothelial glycocalyx (11,14).
PGs and Peritoneal Fibrosis: Although PD is now considered an effective modality of renal replacement therapy, its long-term success is limited by progressive deterioration in the structural integrity of the peritoneal membrane, with a subsequent decline in peritoneal transport function. One of the main reasons for PD technique failure is the development of submesothelial thickening, leading to peritoneal fibrosis, consequent to prolonged exposure to bioincompatible PD solutions. In the extracellular matrix, PGs are major components, and they have diverse biologic functions, including binding and sequestration of growth factors and regulation of collagen fibrillogenesis (7).
Our group has previously demonstrated that decorin and biglycan are the PGs predominantly synthesized by HPMCs (11). The functional importance of these PGs in the peritoneum remains to be elucidated. Increasing evidence suggests that decorin and biglycan regulate cell proliferation through their ability to interact with growth factors and cytokines (16). Of particular interest and potential relevance to the control of peritoneal fibrosis is the ability of decorin to bind transforming growth factor β1 (TGF-β1) via its core protein, and in doing so, to neutralize the biologic activity of that growth factor, possibly by preventing it from binding to its cell-surface receptor. Thus, decorin may act as a natural antagonist and regulator of TGF-β1 activity (17).
Decorin has also been shown to interact with collagen and to prevent collagen fibrillogenesis (18). In the PD setting, such an interaction would prevent induction of collagen synthesis and deposition in the submesothelium, thus preventing peritoneal fibrosis.
The functions of biglycan are largely unknown. However, given that both biglycan and decorin belong to the same family of small, leucine-rich PGs, biglycan may also play a crucial role in the control of collagen fibrillogenesis and fibrosis.
In an animal model of experimental glomerulonephritis, increased TGF-β1 secretion was shown to be associated with induction of decorin and biglycan (19). It is therefore possible that TGF-β1 regulates its own synthesis in an autocrine manner through the upregulation of decorin and biglycan. Our group recently demonstrated that elevated glucose concentrations analogous to those found in PD fluids induced TGF-β1 secretion in cultured HPMCs with a concomitant increase in decorin synthesis (Chan TM, Chen X, Yung S. Unpublished observation). The ability of HPMCs to upregulate synthesis of decorin and biglycan may represent an adaptive process that confers to the peritoneum a defense mechanism against peritoneal membrane thickening during chemical or bacterial injury—for example, from unphysiologic PD solution and peritonitis respectively. That adenovirus-mediated gene transfer of decorin can reduce peritoneal collagen synthesis in an animal model of PD lends support to the latter hypothesis (20).
PGs and Mesothelial Permselectivity: Basement-membrane PGs are found at the periphery of cells and belong predominantly to the heparan sulfate family. The best studied are perlecan and agrin, which are found in the glomerular basement membrane, where they regulate the passage of proteins across the membrane (21).
Basement-membrane PGs have distinct biologic functions ranging from maintenance of basement membrane homeostasis to the binding, sequestering, and modulation of growth factor activity (21). Emerging evidence suggests that basement membrane PGs can function as both pro- and anti-angiogenic mediators. In this respect, heparan sulfate can, through its N-terminal, stimulate angiogenesis by binding to and concentrating growth factors in the vicinity of its cell-surface receptors. By contrast, basement membrane heparan sulfates can use the same mechanism to reduce angiogenic signaling by restricting the diffusion of growth factors though cells (21).
Staining of peritoneal biopsies from patients commencing PD showed perlecan expression in the mesothelium and basal lamina. In peritoneal samples, perlecan expression was observed to decrease with increasing time on PD, consequent to reduced synthesis mediated in part by induction of TGF-β1 by elevated glucose (13). The functional role of perlecan in the peritoneal membrane remains to be fully elucidated, but it may possibly play a role in preserving the mechanical and functional integrity of the peritoneum and in maintaining the selective charge barrier of the peritoneal membrane. That Gotloib and colleagues observed increased transperitoneal passage of proteins as a result of reduced anionic sites within the mesothelium and the underlying basement membrane consequent to chemical or bacterial injury strengthens the case for perlecan's role in the selective charge barrier of the peritoneum (2,3).
PG–Chemokine Interactions in the Peritoneum: The continuous exposure of the peritoneal cavity to bioincompatible PD solutions elicits a chronic inflammatory response, exacerbated by episodes of peritonitis. Rapid recruitment of leukocytes from the circulation to the site of injury is a ubiquitous feature of any inflammatory response and involves the interaction of numerous molecules. Heparan sulfate and dermatan sulfate PGs have been implicated in the extravasation process and establishment of chemotactic gradients (7,22). Membrane-bound and soluble PGs exhibit opposite effects on chemokine receptor binding and may represent an approach to modulating the inflammatory response (23,24). Changes in PG synthesis as a result of chemical, bacterial, or surgical injury may alter recruitment of immune cells and the role that they play during inflammatory responses (7).
ROLE OF HYALURONAN IN THE PERITONEUM
Hyaluronan is a ubiquitous macromolecule synthesized in all mesenchymal
cells by one of three different but related hyaluronan synthases—namely,
HASI, HASII, and HASIII. In its native state, hyaluronan exhibits a molecular
weight greater than 106 Da and participates in the regulation of
water homeostasis and matrix remodeling
(25). Because of its charged
residues, it can attract many water molecules and thus act as a space filler,
a hydrated matrix through which cells migrate, and a lubricant
(25). Hyaluronan is a
component of the mesothelial glycocalyx and protects the mesothelium from
abrasion and adhesion
(10).
Hyaluronan is observed in the first wash-out following catheter insertion in new PD patients, suggesting that part of the hyaluronan is removed from the mesothelial glycocalyx (14). Effluent hyaluronan levels are increased in established PD patients and are further upregulated during episodes of peritonitis (14). Because serum hyaluronan levels cannot account for the elevated levels in PD effluent, increased local peritoneal synthesis of hyaluronan has been suggested following chronic inflammation during PD. In this respect, our group and others have shown that peritoneal mesothelial cells and fibroblasts can synthesize hyaluronan in culture and that hyaluronan levels are increased after stimulation with spent dialysis effluent or proinflammatory cytokines (14,15,26–28). Increased hyaluronan synthesis has also been observed in HPMCs participating in the remesothelialization of a wounded monolayer of HPMCs in vitro, and this increase is predominantly localized to cells entering the injured site, the phenotype of those cells having undergone epithelial-to-mesenchymal transdifferentiation (26).
Successful repair of tissue injury requires a coordinated host response to limit the extent of damage. High molecular weight hyaluronan can be depolymerized to low molecular weight hyaluronan during inflammatory processes (29). These low molecular weight hyaluronan fragments possess biologic functions that are distinct from those of the parent molecule and that have been demonstrated to induce multiple signaling cascades, to enhance fibroblast proliferation, to increase matrix synthesis, and to induce secretion of monocyte chemoattractant protein-1 and interleukin-8, thereby assisting in the formation of a chemotactic gradient and the recruitment of infiltrating cells to sites of injury (30–32).
BENEFICIAL EFFECT OF GAGs IN PD
Because PGs have been implicated in a number of inflammatory events,
molecules or peptides that interfere with their function have considerable
potential as antiinflammatory agents. Heparin is added to PD solutions to
prevent fibrin formation. In addition to preventing fibrin production and
anti-thrombin activity, heparin possesses anti-inflammatory properties that
may be beneficial for PD patients. Our group has demonstrated that the
addition of heparin to HPMCs in culture can abrogate the reduction in perlecan
synthesis mediated by elevated glucose (Chan TM, Chen X, Yung S. Unpublished
observation). Furthermore, in a clinical trial, intraperitoneal administration
of GAGs ameliorated functional and morphologic changes in an experimental
model of peritoneal fibrosis
(33) and improved peritoneal
transport characteristics and inflammation
(34).
Supplementation of PD fluids with high molecular weight hyaluronan has been shown to have beneficial effects on the peritoneum by reducing intraperitoneal inflammation and PD fluid absorption and increasing net ultrafiltration (35–37). Independent researchers have also demonstrated that supplementation of PD solutions with N-acetylglucosamine increases net ultrafiltration, reduces peritoneal permeability to proteins, lowers blood glucose and insulin levels, and reduces peritoneal inflammation (38,39). These changes are associated with a concomitant increase in hyaluronan synthesis in the peritoneal interstitium. In contrast, although Flessner et al. also observed similar changes in peritoneal permeability to protein and in hyaluronan deposition in the peritoneal interstitium of animals infused with N-acetylglucosamine, they demonstrated that such changes were associated with increased angiogenesis and peritoneal fibrosis (40). These discrepancies between structural modifications of the peritoneum may relate to the duration and concentration of N-acetylglucosamine to which the peritoneum was exposed.
|
CONCLUSIONS |
|---|
|
TOPABSTRACTDISCUSSIONCONCLUSIONSREFERENCES |
|---|
|
ACKNOWLEDGMENTS |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTDISCUSSIONCONCLUSIONSREFERENCES |
|---|
to nitric oxide–producing cells: a novel
function for mast cells. J Immunol 2000;164
: 573-9.This article has been cited by other articles:
|
|
 |
|
  M. Mizutani, Y. Ito, M. Mizuno, H. Nishimura, Y. Suzuki, R. Hattori, Y. Matsukawa, M. Imai, N. Oliver, R. Goldschmeding, et al. Connective tissue growth factor (CTGF/CCN2) is increased in peritoneal dialysis patients with high peritoneal solute transport rate Am J Physiol Renal Physiol, March 1, 2010; 298(3): F721 - F733. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Fraser and N. Topley Altering peritoneal membrane function: removing the GAG? Nephrol. Dial. Transplant., November 1, 2009; 24(11): 3271 - 3273. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Baintner Inflammatory ascites formation induced by macromolecules in mice and rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2009; 297(1): R218 - R223. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
