Altering peritoneal membrane function: removing the GAG?

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]. 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, unbranched 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. 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