Effect of high glucose on peritoneal mesothelial cell biology

Objective:This study reviews evidence that implicates high glucose (HG) in the pathogenesis of peritoneal fibrosis and proposes mechanisms potentially involved in the HG-induced peritoneal fibrosis that is observed in long-te rm peritoneal dialysis (PD) patients. Design: Selected Western literature is reviewed, examining the effect of HG on rat or human peritoneal mesothelial cell (HPMC) biology with particular reference to extracellular matrix (ECM) gene expression and protein synthe sis. Results: HG up-regulated the expression of monocyte chemotactic peptide-1 ( MCP-1), transforming growth factor beta 1 (TGF beta 1), and fibronectin mes senger RNAs (mRNAs) and proteins. These HG-induced upregulations were effec tively blocked by the inhibition of protein kinase C (PKC). In addition, cy tosolic reactive oxygen species (ROS) rapidly increased in HPMC cultured un der HG, and treatment with antioxidant effectively inhibited HG-induced fib ronectin protein synthesis by HPMC. Conclusion: Continuous exposure of the peritoneal membrane to HG may induce changes in HPMC biology, leading to excessive deposition of ECM and perito neal injury. HG-induced activation of diacylglycerol PKC (DAG-PKC) plays a major role in up-regulation of MCP-1,TGF beta 1,and fibronectin synthesis b y HPMC cultured under HG. In addition, ROS, recently recognized as signalli ng molecules, are rapidly generated in HPMC as a result of increased glucos e metabolism and may prove to be an important mediator of HG-induced perito neal injury.