Peritoneal mesothelial cell biology in peritoneal dialysis
ABSTRACT Progressive peritoneal membrane hyperpermeability, ultrafiltration failure, and peritoneal fibrosis have been observed in long-term peritoneal dialysis (PD) patients, and these alterations in peritoneal structure and function may be responsible for the poor technique survival in PD. While frequent and/or severe peritonitis can result in alterations of the peritoneum, continuous exposure of the peritoneum to PD solutions may also adversely affect peritoneal structure and function. Peritoneal mesothelial cells (PMC) are directly and continuously exposed to unphysiological components of PD solution. Low pH, lactate, hyperosmolality, and glucose degradation products (GDP) reduce PMC viability and proliferation. High glucose, GDP, and advanced glycation end products (AGE) upregulate vascular endothelial growth factor (VEGF), monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, and extracellular matrix protein expression by PMC, and may thus lead to peritoneal hyperpermeability, ultrafiltration failure, and peritoneal fibrosis, as observed in long-term PD. Activation of diacylglycerol (DAG)-protein kinase C (PKC) and generation of reactive oxygen species (ROS) are important upstream signalling events in high glucose-induced PMC activation. Thus, strategies to inhibit high glucose-induced PKC activation and ROS generation and the use of new PD solutions with non-glucose osmotic agents, pH neutral solutions, or solutions containing low GDP may allow better preservation of the structural and functional integrity of the peritoneal membrane during long-term PD.
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ABSTRACT: Oxidative stress has been known to play an important role in the development and progression of diabetic nephropathy, but the intracellular signal transduction pathways regulated by reactive oxygen species (ROS) have not been clearly defined. High glucose (HG) induces intracellular ROS directly via glucose metabolism and auto-oxidation and indirectly through the formation of advanced glycation end products and their receptor binding. ROS mimic the stimulatory effects of HG and upregulate transforming growth factor-â1, plasminogen activator inhibitor-1, and extracellular matrix (ECM) proteins by glomerular mesangial cells, thus leading to mesangial expansion. ROS activate other signaling molecules, such as protein kinase C and mitogenactivated protein kinases and transcription factors, such as nuclear factor-êB, activator protein-1, and specificity protein 1 leading to transcription of genes encoding cytokines, growth factors, and ECM proteins. Finally, various antioxidants inhibit mesangial cell activation by HG and ameliorate features of diabetic nephropathy. These findings qualify ROS as intracellular messengers and as integral glucose-signaling molecules in glomerular mesangial cells in diabetic nephropathy. With this new concept, ROS assume a greater importance in the pathogenesis of diabetic nephropathy. Future studies elucidating other downstream-signaling molecules activated by ROS in mesangial and other renal cells will allow us to understand the final cellular responses to HG, such as proliferation, differentiation, apoptosis, and ECM accumulation. With this new information, we should be able to develop strategies for a more rational treatment of diabetic nephropathy.Current Diabetes Reports 04/2012; 1(3):282-287. · 3.17 Impact Factor
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ABSTRACT: Effect of lactate-buffered peritoneal dialysis fluids on human mesothelial cell interleukin-6 and prostaglandin synthesis. The present study focused on the evaluation of constitutive and cytokine-stimulated human peritoneal mesothelial cell (HPMC) IL-6 and 6-keto-PGF1, release following pre-exposure to peritoneal dialysis fluid (PDF). Exposure of HPMC to PDF pH 5.2 resulted in a time-dependent increase in cell cytotoxicity [as assessed by lactate dehydrogenase (LDH) release] and concomitant inhibition of constitutive and IL-1 stimulated IL-6 and 6-keto-PGF1 synthesis. After 15 minutes of exposure to PDF constitutive and IL-1 stimulated IL-6 release were reduced by 32.0 9.7% and 76.0 7.4% (N = 6, P < 0.046 and P < 0.027, respectively). PCR amplification of reverse transcribed mRNA from HPMC pre-exposed to PDF pH 5.2 demonstrated suppression of IL-1 stimulated IL-6 and cyclooxygenase (Cox-1 and Cox-2) transcripts. In order to mimic the dialysis cycle in vivo, an in vitro dialysis system was established. HPMC were exposed first to control medium, PDF pH 5.2 or PDF 7.3 for 15 minutes and then sequentially to pooled spent peritoneal dialysis effluent for up to four hours. The cells were subsequently allowed to recover in control medium for 12 hours in the presence or absence of IL-1 or TNF- (both at 1000 pg/ml). There was no evidence of significant cell toxicity as assessed by LDH release during either the 'in vitro dialysis" or 'recovery" phases. Under these conditions short term exposure to PDF pH 5.2 followed by 'in vitro dialysis" resulted in significant inhibition of cytokine stimulated IL-6 (69.6 18.2 vs. 96.7 27.9 pg/g, N = 13; P < 0.020 for IL-1) and 6-keto-PGF1 (197.5 89.2 vs. 289.6 114.5 pg/g, N = 13; P < 0.020 for IL-1) and 6-keto-PGF1 (197.5 89.2 vs. 289.6 114.5 pg/g, N = 13; P < 0.003) release when compared to cells incubated in control medium. Adjustment of the pH of PDF to 7.3 reversed its inhibitory effects. We conclude that short-term exposure to PDF pH 5.2 significantly inhibits HPMC cytokine and prostaglandin release, an effect which appears to be related to its initial pH. Repeated exposure to nonphysiological PDF might impair mesothelial cell function and thus modulate intraperitoneal inflammatory processes.Kidney International - KIDNEY INT. 01/1995; 47(1).
- New England Journal of Medicine 06/1988; 318(20):1315-21. · 51.66 Impact Factor