Increased peritoneal damage in glyoxalase 1 knock-down mice treated with peritoneal dialysis.
BACKGROUND
Peritoneal dialysis (PD) is limited by peritoneal fibrosis and ultrafiltration failure. This is in part caused by the high concentration of glucose degradation products (GDPs) present in PD fluids (PDF) as a consequence of heat sterilization. Existing research in long-term PD has mainly dealt with the toxicity induced by GDPs and the development of therapeutic strategies to reduce the cellular burden of GDPs. Currently, there are few data regarding the potential role of detoxification systems of GDP in PD. In this study, the role of glyoxalase 1 (Glo1), the major detoxification pathway for dicarbonyl-derived GD such as methylglyoxal (MG) and glyoxal (Gx), was investigated in vivo using heterozygous knock-down mice for Glo1 (Glo1(-/+)).


METHODS
Wild-type (WT) and Glo1(-/+) mice were repeatedly treated with PDF containing low and high amounts of GDP, particularly with respect to the content of dicarbonyls. After 12 weeks of treatment with PDF, peritoneal damage and function were evaluated.


RESULTS
Glo1(-/+) mice treated with PDF showed increased formation of advanced glycation endproduct (AGE) when compared with WT mice, particularly the Gx-derived AGE, carboxymethyl-lysine. This was associated with increased inflammation, neovascularization, increased peritoneal fibrosis and impaired peritoneal function.


CONCLUSIONS
This study suggests a pivotal and underestimated role for Glo1 as a detoxifying enzyme in GDP-associated peritoneal toxicity in PD. The indirect and direct modulation of Glo1 may therefore offer a new therapeutic option in prevention of GDP-induced peritoneal damage in PD.
Department of Nephrology, University of Heidelberg, Heidelberg, Germany Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
Lars P
LP
Kihm
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Sandra
S
Müller-Krebs
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Sandra
S
Holoch
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Svenja
S
Schmuck
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Luis E
LE
Becker
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Michael
M
Brownlee
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Martin
M
Zeier
Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
Thomas H
TH
Fleming
Department of Internal Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
Peter P
PP
Nawroth
Department of Nephrology, University of Heidelberg, Heidelberg, Germany.
Vedat
V
Schwenger
D000818:Animals; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007791:Lactoylglutathione Lyase / Q000502:physiology*; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; C048496:N(6)-carboxymethyllysine; D007791:Lactoylglutathione Lyase; D008239:Lysine
glucose degradation products; glyoxalase; methylglyoxal; mice; peritoneal dialysis