long - term peritoneal dialysis ( pd ) is associated with progressive increase in the thickness of peritoneal membrane , predominantly in the submesothelial compact collagenous zone ( 1 ) , and membrane hyperpermeability ( 2 ) .
the mechanisms involved in these structural and functional changes remain unclear , but prolonged exposure of the membrane to conventional pd solution containing high concentrations of glucose and glucose degradation products ( gdp ) may play an important role .
epithelial - mesenchymal transition ( emt ) of epithelial cells , characterized by loss of epithelial cell characteristics and gain of ecm - producing myofibroblast characteristics , is an important mechanism involved in tissue fibrosis ( 3 - 6 ) .
recent data ( 7 - 9 ) suggest that human peritoneal mesothelial cells ( hpmc ) undergo emt during pd and that emt may play an important role in the development and progression of peritoneal fibrosis leading to failure of peritoneal membrane function
. this brief review will discuss the mechanisms of emt and suggest strategies for the prevention of emt and preservation of peritoneum during long - term pd .
accumulating evidence implicates emt as a potential mechanism for the development and progression of peritoneal fibrosis during long - term pd leading to failure of peritoneal membrane function .
( 7 ) first reported that peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype soon after pd was initiated with a decrease in the expression of cytokeratin and e - cadherin through induction of the transcriptional repressor snail .
( 8) demonstrated that intra - peritoneal administration of adenovirus - mediated transforming growth factor-1 ( tgf-1 ) increases peritoneal expression of genes associated with fibrosis and emt including collagen i , -smooth muscle actin ( -sma ) , and snail , suggesting that emt occurs in vivo after tgf-1 overexpression in the peritoneum .
nonepithelioid mesothelial cells from spent dialysate produces a greater amount of vegf ex vivo than epithelioid - like mesothelial cells ( 9 ) , suggesting that emt may also have a role in peritoneal hyperpermeability .
it is therefore important to clearly understand the mechanisms involved in emt during pd in order to provide a novel therapeutic strategy to prevent emt and peritoneal fibrosis .
we have shown that high glucose ( 10 ) and glucose - based pd solution ( 11 ) induce generation of reactive oxygen species ( ros ) in cultured hpmc and that ros generated by glucose - based conventional pd solution is responsible for peritoneal neoangiogenesis , membrane hyperpermeability , and peritoneal fibrosis in rats treated with glucose - based pd solutions ( 12 ) .
we ( 13 ) recently reported that 1 ) high d - glucose , h2o2 , and glucose - based pd solutions upregulate -sma and downregluate e - cadherin in hpmc , 2 ) antioxidants , n - acetylcystein ( nac ) and catalase , effectively reverse high glucose - induced -sma and e - cadherin expression in hpmc , and that 3 ) prolonged exposure of rat peritoneum to glucose - based pd solution upregulates -sma expression in the peritoneum , which is effectively inhibited by nac .
all these data suggest that ros plays a major role in peritoneal emt induced by high glucose and glucose - based pd solutions .
this is consistent with our previous observation that ros is involved in tgf-1-induced emt in renal tubular epithelial cells ( 14 ) .
gdp have been suggested to play a role in inducing emt . spent dialysate obtained at 12 months after the initiation of pd using solutions containing low gdp had a significantly fewer number of fibroblast - dominant cells compared to effluent obtained from patients using pd solutions containing high gdp ( 15 ) . given that gdp signal through ros ( 16 ) , it is conceivable that ros mediate gdp - induced emt in the peritoneum .
rapamycin was shown to effectively inhibit tgf-1-induced emt in cultured hpmc , suggesting the involvement of a mammalian target of rapamycin ( mtor ) in emt ( 17 ) .
the phosphatidylinositol 3-kinase ( pi3-k)/akt / mtor pathway has recently been recognized as an important pathway in diabetic renal injury . high glucose activates the akt / mtor pathway in mesangial cells ( 18 ) , both akt and mtor are increased in diabetic kidneys ( 19 ) , and low - dose rapamycin slows the progression of diabetic renal injury including -sma overexpression and matrix accumulation ( 20 ) .
in cultured hpmc , treatment with antioxidants effectively inhibited high glucose - induced ros generation ( 10 ) and emt ( 13 ) . in an animal model of pd , intraperitoneal administration of nac effectively prevented -sma expression in the peritoneum ( 13 ) as well as peritoneal membrane thickening , neoangiogenesis , and hyperpermeability ( 12 ) .
these observations strongly suggest that ros is an important therapeutic target in peritoneal emt and structural and functional alterations in peritoneum during long - term pd .
since tgf-1 is the major inducer of emt , strategies inhibiting tgf-1 signaling is a plausible way to prevent emt during pd .
bone morphogenetic protein-7 ( bmp-7 ) , a 35 kda homodimeric protein and a member of tgf- superfamily , is an endogenous antifibrotic protein that prevents renal fibrosis in ureteral obstruction ( 21 ) , diabetic nephropathy ( 22 ) , and nephrotoxic serum nephritis ( 23 ) . we ( 24 ) recently observed that hpmc constitutively express bmp-7 , that high glucose , glucose - based pd solution , and tgf-1 downregulated bmp-7 expression in hpmc , and that overexpression of bmp-7 in hpmc prevented emt induced by tgf-1 , suggesting bmp-7 as a potential therapeutic strategy for preventing emt of hpmc .
this is consistent with a recent report ( 25 ) that ex vivo treatment with bmp-7 reversed in vivo and ex vivo emt of hpmc . bmp-7
rapamycin can prevent tgf-1-induced emt in hpmc ( 17 ) presumably through inhibition of high glucose - induced activation of the mtor pathway ( 18 ) .
clinical trials are needed to prove the efficacy of these experimental strategies in pd patients .
cell culture and animal studies suggest that high glucose , gdp , glucose - based pd solution , tgf-1 , loss of bmp-7 , and activation of the mtor pathway induce emt of hpmc and that antioxidants , bmp-7 , and rapamycin may prevent emt and allow better preservation of structural and functional integrity of the peritoneal membrane during long - term pd .
further studies elucidating the mechanisms involved in emt of hpmc and clinical trials may provide new therapeutic strategies for inhibiting peritoneal fibrosis during long - term pd .
 a growing body of evidence indicates that epithelial - mesenchymal transition ( emt ) of human peritoneal mesothelial cells ( hpmc ) may play an important role in the development and progression of peritoneal fibrosis during long - term peritoneal dialysis ( pd ) leading to failure of peritoneal membrane function . here , we review our own observations and those of others on the mechanisms of emt of hpmc and suggest potential therapeutic strategies to prevent emt and peritoneal fibrosis during long - term pd . 
 we found that high glucose and h2o2 as well as transforming growth factor-1 ( tgf-1 ) induced emt in hpmc and that high glucose - induced emt was blocked not only by inhibition of tgf-1 but also by antioxidants or inhibitors of mitogen - activated protein kinases ( mapk ) . 
 since mapks are downstream target molecules of reactive oxygen species ( ros ) , these data suggest that high glucose - induced generation of ros and subsequent mapk activation mediate high glucose - induced emt in hpmc . 
 we and others also observed that bone morphogenetic protein-7 ( bmp-7 ) prevented emt in hpmc . 
 glucose degradation products ( gdp ) were shown to play a role in inducing emt . 
 involvement of a mammalian target of rapamycin ( mtor ) in tgf-1-induced emt has also been proposed in cultured hpmc 
 . a better understanding of the precise mechanisms involved in emt of hpmc may provide new therapeutic strategies for inhibiting peritoneal fibrosis in long - term pd patients . 