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THE ROLE OF THE GLYOXALASE PATHWAY IN REDUCING MESOTHELIAL TOXICITY OF GLUCOSE DEGRADATION PRODUCTS

Katarzyna Korybalska¹, Justyna Wisniewska-Elnur¹, Joanna Trómiska¹, Achim Jörres², Andrzej Brborowicz¹ and Janusz Witowski^1,2

Department of Pathophysiology,¹ University Medical School, Pozna, Poland; Department of Nephrology and Medical Intensive Care,² Universitätsmedizin Charité, Campus Virchow-Klinikum, Berlin, Germany

Correspondence to: J. Witowski, Department of Pathophysiology, University Medical School,wicickiego 6, 60-781 Pozna, Poland.
jwitow{at}amp.edu.pl

• Background: The glucose degradation products (GDP) present in conventional peritoneal dialysis fluids (PDF) may exert adverse effects toward human peritoneal mesothelial cells (HPMC). Some GDP can be detoxified by the glyoxalase/glutathione pathway. It has been shown that the addition of glyoxalase I (GLO-I) and reduced glutathione (GSH) to PDF effectively eliminates GDP. We have therefore examined the GLO-I/GSH system in HPMC and assessed the impact of GLO-I/GSH-treated PDF on the viability and function of HPMC.
  
• Methods: Heat-sterilized PDF (H-PDF) was incubated in the presence or absence of GLO-I and GSH for 1 hour at 37°C, and then mixed with an equal volume of serum-free M199 medium and applied to HPMC in culture. After 24 hours, HPMC were assessed for viability, the release of interleukin-6, GLO-I activity, and cellular glutathione. The effects were compared to those exerted by filter-sterilized PDF (F-PDF), which was devoid of GDP.
  
• Results: Exposure of HPMC to H-PDF resulted in reduced GLO-I activity, GSH depletion, and a decrease in cell viability. Pretreatment of H-PDF with either a combination of GLO-I and GSH or GSH alone markedly reduced inhibitory effects of H-PDF toward HPMC, as measured by cell viability and interleukin-6 generation. Exposure of HPMC to the GSH precursor L-2-oxothiazolidine-carboxylic acid increased cellular GSH and prevented the loss of GLO-I activity in response to H-PDF.
  
• Conclusions: Exposure to conventional GDP-rich PDF impairs the activity of the glyoxalase/glutathione system in HPMC. Pretreatment of PDF with GSH or replenishment of cellular GSH protects HPMC against GDP-mediated toxicity.
  

KEY WORDS: Glucose degradation products; glyoxalase; glutathione; dialysis fluids; mesothelial cells; biocompatibility.

Received 12 May 2004; accepted 31 July 2005.

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