Glucose-mediated induction of TGF-beta 1 and MCP-1 in mesothelial cells in vitro is osmolality and polyol pathway dependent.
BACKGROUND
Glucose is converted to sorbitol and then to fructose via the polyol pathway that has been implicated in the pathogenesis of organ damage. The contribution of the polyol pathway to mesothelial cell activation has, however, not been fully determined.


METHODS
The effect of increasing glucose concentrations on transforming growth factor-beta 1 (TGF-beta 1) and monocyte chemoattractant protein-1 (MCP-1) secretion by human peritoneal mesothelial cells (HPMC) was examined. The importance of the polyol pathway was identified by its specific inhibition with an aldose reductase inhibitor.


RESULTS
Incubation of HPMC with 5 to 100 mmol/L glucose resulted in an induction of aldose reductase mRNA and intracellular sorbitol accumulation accompanied by the induction of TGF-beta 1 and MCP-1 mRNA expression and protein secretion. Mannitol at the same concentrations also induced aldose reductase, TGF-beta 1 and MCP-1 mRNA and protein expression but at a lower level than glucose. Sorbinil dose-dependently reduced both intracellular sorbitol levels (79.8% reduction of 60 mmol/L D-glucose induced intracellular sorbitol with 100 micromol/L sorbinil (N = 3, P < 0.01) and glucose-induced TGF-beta 1 and MCP-1 secretion. Mannitol induced TGF-beta 1 and MCP-1 secretion was not reduced by sorbinil. The addition of 15 to 40 mmol/L sodium lactate, either alone or in the presence of D-glucose enhanced TGF-beta 1 and MCP-1 secretion, which was inhibited by sorbinil. In contrast, sodium pyruvate appeared to antagonize D-glucose-induced TGF-beta 1 and MCP-1 secretion.


CONCLUSIONS
These data suggest that the polyol pathway and osmolality contribute to the regulation of HPMC function by glucose. Control of polyol pathway activation might reduce glucose-mediated damage to the peritoneal membrane and promote its long-term survival.
Wong
Teresa Y H
TY
Institute of Nephrology, University of Wales College of Medicine, Cardiff, United Kingdom.
Phillips
Aled O
AO
Witowski
Janusz
J
Topley
Nicholas
N
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D004848:Epithelium; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007064:L-Iditol 2-Dehydrogenase / Q000235:genetics; D009994:Osmolar Concentration; D010530:Peritoneal Dialysis; D010537:Peritoneum / Q000166:cytology / Q000502:physiology*; D011108:Polymers / Q000378:metabolism*; D019289:Pyruvic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D012965:Sodium Chloride / Q000494:pharmacology; D019354:Sodium Lactate / Q000494:pharmacology; D013012:Sorbitol / Q000493:pharmacokinetics; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D018932:Chemokine CCL2; D011108:Polymers; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C024617:polyol; D012965:Sodium Chloride; D013012:Sorbitol; D019289:Pyruvic Acid; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase; D005947:Glucose; D019354:Sodium Lactate