3,4-Dideoxyglucosone-3-ene as a mediator of peritoneal demesothelization.
BACKGROUND
The mesothelium contributes significantly to the functional, structural and homeostatic properties of the peritoneum. Bioincompatible peritoneal dialysis solutions contribute to mesothelial cell loss during chronic peritoneal dialysis. Cell death has been implicated in mesothelial cell loss, but the molecular mechanisms have not been adequately characterized. We now report the modulation of mesothelial cell death by the glucose degradation product 3,4-dideoxyglucosone-3-ene (3,4-DGE).


METHODS
Human mesothelial cells were cultured from the effluents of stable dialysis patients. Apoptosis was quantified in cultured mesothelial cells and in peritoneal effluents. Confocal microscopy and inhibitors were used to assess molecular mechanisms.


RESULTS
Peritoneal dialysis solutions with a high content of both glucose and glucose degradation products, but not those with low glucose degradation product content, induced mesothelial cell apoptosis and loss of cell viability in culture and in vivo. 3,4-DGE also induced mesothelial cell apoptosis. Apoptosis induced by peritoneal dialysis solutions and 3,4-DGE was associated with oligomerization of Bax at mitochondria and caspase activation. Bax antagonism prevented caspase activation, apoptosis and cell death. The pancaspase inhibitor zVAD was also protective.


CONCLUSIONS
3,4-DGE and peritoneal dialysis solutions with a high content in glucose degradation products induce mesothelial cell apoptosis by a Bax-dependent mechanism. This could contribute to chronic demesothelization in peritoneal dialysis.
Unidad de Diálisis, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Av. Reyes Católicos 2, 28040 Madrid, Spain. bsantamaria@fjd.es.
Beatriz
B
Santamaría
Alvaro C
AC
Ucero
Ana
A
Reyero
Rafael
R
Selgas
Marta
M
Ruiz-Ortega
Marina
M
Catalán
Jesús
J
Egido
Alberto
A
Ortiz
D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D015314:Dialysis Solutions / Q000378:metabolism / Q000633:toxicity; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010531:Peritoneal Dialysis, Continuous Ambulatory / Q000009:adverse effects; D010537:Peritoneum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D011753:Pyrones / Q000378:metabolism* / Q000633:toxicity*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C504711:3,4-dideoxyglucosone-3-ene; C494826:BAX protein, human; D015314:Dialysis Solutions; D011753:Pyrones; D051028:bcl-2-Associated X Protein; D020169:Caspases; D005947:Glucose