Skip Navigation

Nephrology Dialysis Transplantation 2009 24(11):3271-3273; doi:10.1093/ndt/gfp440
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Fraser, D. J.
Right arrow Articles by Topley, N.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fraser, D. J.
Right arrow Articles by Topley, N.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Altering peritoneal membrane function: removing the GAG?

Donald J. Fraser1 and Nicholas Topley2

1 Institute of Nephrology 2 Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK

Correspondence and offprint requests to: Donald J. Fraser; E-mail: fraserdj{at}cf.ac.uk

Peritoneal dialysis (PD) is a highly effective and convenient mode of renal replacement therapy. The success of PD depends on maintaining the structural and functional integrity of the peritoneal membrane. The outer (serosal) part of the peritoneal membrane consists of a monolayer of mesothelial cells, which provide a low-friction surface, allowing internal organs to move relative to one another. The membrane acts as a selective permeability barrier, regulating the passage of water and solutes between the intravascular compartment and the peritoneal cavity. Duration of PD is often limited by peritoneal membrane failure, associated with increased solute transport, ultrafiltration dysfunction and with characteristic degenerative changes in the peritoneal membrane, including mesothelial cell loss, accumulation of sub-mesothelial extracellular matrix and vasculopathy (Figure 1) [1].


Figure 1
View larger version (25K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Pictorial representation of the time course of changes in the peritoneal membrane during peritoneal dialysis. Alterations driven by continuous exposure to dialysis solutions, episodic infection and local chronic peritoneal inflammation lead to extracellular matrix changes (protein, proteoglycan deposition) and vascular alterations (angiogenesis and vasculopathy). Key cellular events are epithelial to mesenchymal transition (of mesothelial cells to myofibroblasts) and the activation of resident peritoneal fibroblast populations. The contribution of alterations to GAG in these processes remain to be fully defined. Images presented courtesy of the peritoneal biopsy registry.

 
The role of glycosaminoglycans (GAG) in peritoneal membrane function and failure has not been extensively studied, although their potential roles are the subject of recent excellent reviews [2,3]. GAG are long, unbran- ched polysaccharides. The majority of GAG-containing molecules, including decorin and versican, are proteoglycans, which consist of GAG chains attached to a protein core (Figure 2). Hyaluronan is an important exception, consisting of a simple repeating disaccharide. GAG have an extensive ability to bind water, leading to highly hydrated molecules that lend themselves to various structural roles in connective tissues [4]. However, GAG otherwise vary widely in structure and function. Mesothelial cells cultured in vitro synthesize and secrete GAG [5], and GAG are found in PD effluent fluid following dialysis exchange, particularly relatively small proteoglycans such as decorin and bikunin [5]. The physical properties of GAG suggest that they may play a role in maintaining the integrity of the mesothelial monolayer, by providing a hydrated and low friction surface, allowing internal organs to move relative to one another, and avoiding adhesion formation. To date, however, there is a paucity of data on the expression of GAG within the peritoneal membrane.


Figure 2
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Structures of versican, decorin, and hyaluronan. Versican and decorin consist of a core protein with attached polysaccharide and oligosaccharide chains. Hyaluronan is a linear polysaccharide. Chondroitin/dermatan sulphate chains consist of up to 100 sugar molecules, with variable sulphation patterns. Hyaluronan is a linear polymer of up to 50 000 sugar molecules, which are unsulphated.

 
In this issue, Osada et al. [6] have examined the expression of proteoglycans in peritoneal membrane biopsies from peritoneal dialysis patients and from normal controls. They examined the expression of decorin, versican and hyaluronan in samples from eight patients at the initiation of PD, nine long-term PD patients without evidence of peritonitis and five long-term PD patients who had peritonitis for more than one month, and compared these data to expression patterns in three normal subjects.

Decorin has a molecular weight of approximately 100 kD. It is widely expressed in connective tissue, where it binds particularly to type I collagen, and plays an important role in ECM organisation, such that mice null for decorin exhibit abnormalitites of collagen fibre formation, and have fragile skin [7]. Decorin also regulates signalling pathways, for example, by down regulating epidermal growth factor receptor [8], and by binding to the prototypic profibrotic cytokine, transforming growth factor beta-1 (TGF-β) and inhibiting its bioactivity [9]. In the current study, decorin expression was highest in peritoneal membrane samples from normal individuals, lower at onset of PD and lowest in long-term PD patients. In long-term PD patients with active peritonitis, decorin was not detectable. The major interest in decorin as a potential anti-fibrotic molecule has arisen largely from studies demonstrating that, secondary to its inhibitory action on TGF-β signalling, it is effective in limiting renal injury in rodent glomerulonephritis when injected [10] or systemically over-expressed [11]. Therefore, one possible consequence of loss of decorin expression in long-term PD might be enhanced TGF-β signalling, suggesting that such a loss of decorin expression might play a causative role in driving peritoneal fibrosis. Indeed, in a murine model of chronic PD fluid infusion, over-expression of decorin limited collagen accumulation, although it is important to note that, in this study at least, this did not lead to any significant changes in peritoneal ultrafiltration [12].

Hyaluronan is a linear GAG that can vary in size from as little as 5 kD to as much as 20 000 kD. It acts as the major lubricant within synovial fluid, and is widely expressed in other connective tissues and extracellular matrices [13]. Interactions of many hyaluronan-binding proteins are important in modelling the extracellular matrix (ECM) in various locations in the body [13]. Through interaction with its major cell surface receptors, including CD44 and RHAMM, hyaluronan also plays a key role in cellular movement and proliferation, in response to injury and inflammation [14], and in malignancy [15]. In the current study, hyaluronan was weakly expressed in normal subjects and at initiation of PD, more readily detectable in biopsies from long-term PD patients, and uniformly strongly present (as evidenced by increased staining) in biopsies from PD patients with ongoing infection. Many proteins bind extracellular HA (the so-called hyaladherins) and modify its function, and cellular responses to HA may vary depending on expression of HA receptors. Variation in the HA chain length can also have profound effects on cellular response to HA, with high-molecular weight HA implicated in cellular proliferation and healing, while low-molecular weight HA may be profoundly pro-inflammatory [16]. The findings of Osada et al. (NDT insert reference) are intriguing, therefore, and suggest that further studies will be required on the molecular nature of peritoneal membrane HA to draw definitive conclusions about its role in normal peritoneal function, and any contribution alteration in its expression might have in the processes that regulate peritoneal fibrogenesis and membrane dysfunction.

Versican exceeds 1000 kD in size and is highly hydrated. It is widely expressed, interacts with hyaluronan and plays a role in maintaining the structure of the extracellular matrix (ECM) [17,18]. Versican is increased in expression in inflammatory and malignant conditions, where its interaction with adhesion molecules appears to play a key role in the homing of inflammatory leukocytes [18], and may be a key component of metastatic progression [19]. In the current study, versican staining was undetectable in normal subjects, and increasingly heavy in biopsies from patients at PD initiation, long-term PD patients, with and without infection. Versican staining was noted predominantly in areas of fibrosis, the elastic lamina of the peritoneum, vascular walls and perivascular regions. It is possible that versican is involved in PD-associated vasculopathy, adoption of a profibrotic phenotype by mesothelial cells, and in recruitment of non-resident inflammatory cells. Consistent with these potential roles, Osada et al. noted an association between versican staining intensity and macrophage influx, alpha-smooth muscle actin ({alpha}-SMA) intensity and matrix metalloproteinase-2 (MMP-2) expression.

This study raises many important questions concerning the role of GAG in peritoneal function and dysfunction. It is tempting to speculate that loss of decorin together with increased expression of versican and hyaluronan in long-term peritoneal dialysis patients, particularly those with longstanding peritonitis, represents acquisition of a ‘pro-fibrotic’ pattern of GAG expression. However, these observations, although of great interest, are based on very small numbers of patient samples, and clearly many more expression and functional studies will be required. Future studies having quantitative measures of GAG expression from larger cohorts of patients with various durations of treatment and defined disease events, particularly data in subjects grouped by measures of peritoneal membrane function, will be essential to tease out the precise, and likely complex, roles of these important molecules in peritoneal pathology.



   Acknowledgments
 
DF is funded by a Welsh Office of Research Development clinician scientist fellowship.

Conflict of interest statement. None declared.

(See related article by S. Osada et al. Alterations in proteoglycan components and histopathology of the peritoneum in uraemic and peritoneal dialysis (PD) patients. Nephrol Dial Transplant 2009; 24: 3504–3512.)



   References
Top
 References
 

  1. Williams JD, Craig KJ, Topley N, et al. Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol (2002) 13:470–479.[Abstract/Free Full Text]
  2. Yung S, Chan TM. Glycosaminoglycans and proteoglycans: overlooked entities? Perit Dial Int (2007) 27(Suppl_2):S104–S109.[Abstract/Free Full Text]
  3. Yung S, Chan TM. Peritoneal proteoglycans: much more than ground substance. Perit Dial Int (2007) 27:375–390.[Abstract/Free Full Text]
  4. Knudson CB, Knudson W. Cartilage proteoglycans. Semin Cell Dev Biol (2001) 12:69–78.[CrossRef][Web of Science][Medline]
  5. Yung S, Thomas GJ, Stylianou E, et al. Source of peritoneal proteoglycans. Human peritoneal mesothelial cells synthesize and secrete mainly small dermatan sulfate proteoglycans. Am J Pathol (1995) 146:520–529.[Abstract]
  6. Osada S, Hamada C, Shimaoka T, et al. Alterations of proteoglycan components and histopathology of the peritoneum in uremic and peritoneal dialysis (PD) patients. Nephrol Dial Transplant (2009) 24:3504–3512.[Abstract/Free Full Text]
  7. Danielson KG, Baribault H, Holmes DF, et al. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol (1997) 136:729–743.[Abstract/Free Full Text]
  8. Zhu JX, Goldoni S, Bix G, et al. Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis. J Biol Chem (2005) 280:32468–32479.[Abstract/Free Full Text]
  9. Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature (1990) 346:281–284.[CrossRef][Medline]
  10. Border WA, Noble NA, Yamamoto T, et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature (1992) 360:361–364.[CrossRef][Medline]
  11. Isaka Y, Brees DK, Ikegaya K, et al. Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat Med (1996) 2:418–423.[CrossRef][Web of Science][Medline]
  12. Margetts PJ, Gyorffy S, Kolb M, et al. Antiangiogenic and antifibrotic gene therapy in a chronic infusion model of peritoneal dialysis in rats. J Am Soc Nephrol (2002) 13:721–728.[Abstract/Free Full Text]
  13. Tammi MI, Day AJ, Turley EA. Hyaluronan and homeostasis: a balancing act. J Biol Chem (2002) 277:4581–4584.[Free Full Text]
  14. Taylor KR, Gallo RL. Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. Faseb J (2006) 20:9–22.[Abstract/Free Full Text]
  15. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer (2004) 4:528–539.[CrossRef][Web of Science][Medline]
  16. Moreland LW. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther (2003) 5:54–67.[Web of Science][Medline]
  17. Zimmermann DR, Ruoslahti E. Multiple domains of the large fibroblast proteoglycan, versican. Embo J (1989) 8:2975–2981.[Web of Science][Medline]
  18. Rahmani M, Wong BW, Ang L, et al. Versican: signaling to transcriptional control pathways. Can J Physiol Pharmacol (2006) 84:77–92.[CrossRef][Web of Science][Medline]
  19. Kim S, Takahashi H, Lin W, et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature (2009) 457:102–106.[CrossRef][Web of Science][Medline]
Received for publication: 13. 7.09
Accepted in revised form: 4. 8.09


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Fraser, D. J.
Right arrow Articles by Topley, N.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fraser, D. J.
Right arrow Articles by Topley, N.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?