The triggering of human peritoneal mesothelial cell apoptosis and oncosis by glucose and glycoxydation products.
BACKGROUND
Peritoneal dialysis fluids (PDFs) have been shown to alter mesothelial cell functions. To further determine the mechanisms involved, we investigated the effects of glucose, glucose degradation products (GDPs) and advanced glycation end products (AGEs) on the inhibition of human peritoneal mesothelial cell (HPMC) proliferation and the induction of apoptosis and oncosis.


METHODS
Four PDF solutions, heat-sterilized dextrose-lactate, filtered dextrose-lactate and heat-sterilized dextrose-bicarbonate-lactate, each containing 15 or 45 g/l glucose, and heat-sterilized icodextrin-lactate, containing 75 g/l icodextrin, were tested. In addition, we analysed the independent and synergistic effects of two glucose compounds, i.e. 3-deoxyglucosone (3-DG), a major GDP, and Nepsilon-(carboxymethyl)-lysine (CML), a high-affinity AGE receptor (RAGE) ligand on HPMC viability. Cell proliferation was measured by methyl-[(3)H]thymidine incorporation. Oncosis was quantified by nuclear propidium iodide (PI) DNA-intercalating capability, and apoptosis by the decrease in mitochondrial transmembrane potential ( triangle up psim).


RESULTS
It was found that heat-sterilized dextrose-lactate inhibited HPMC proliferation to a greater extent than filtered dextrose-lactate, heat-sterilized dextrose-bicarbonate-lactate, or heat-sterilized icodextrin-lactate (P<0.001). Compared to filtered dextrose-lactate, heat-sterilized dextrose-lactate induced a significantly greater degree of apoptosis (P<0.05) and oncosis (P<0.01). Glucose-induced cell death and antiproliferative activity were significantly potentiated by the action of 3-DG or CML-albumin. By blocking the AGE-RAGE interaction recombinant soluble-RAGE reduced the PDF-induced inhibitory effect on cell proliferation (P<0.001) and apoptosis (P<0.05).


CONCLUSIONS
Heat-sterilized PDFs that contain high glucose concentrations and GDPs, which are AGE precursors, reduce cell proliferation, induce mesothelial cell apoptosis and oncosis, and may be involved in peritoneal damage. PDFs containing lower glucose derivative products are more biocompatible.
Boulanger
Eric
E
Laboratoire de Biologie Vasculaire et Cellulaire, INTS, 6 Rue A. Cabanel, 75739 Paris Cedex 15, France. eboulanger@ints.fr
Wautier
Marie-Paule
MP
Gane
Pierre
P
Mariette
Christophe
C
Devuyst
Olivier
O
Wautier
Jean-Luc
JL
D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015314:Dialysis Solutions / Q000009:adverse effects*; D004847:Epithelial Cells / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects*; D005947:Glucose / Q000009:adverse effects* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000009:adverse effects; D006801:Humans; D010530:Peritoneal Dialysis / Q000009:adverse effects; D010537:Peritoneum / Q000187:drug effects*
D015314:Dialysis Solutions; D017127:Glycation End Products, Advanced; D005947:Glucose