3,4-Dideoxyglucosone-3-ene induces apoptosis in renal tubular epithelial cells.
Diabetes complications are caused by hyperglycemia. Hyperglycemia results in increased concentrations of glucose degradation products. The study of peritoneal dialysis solution biocompatibility has highlighted the adverse effects of glucose degradation products. Recently, 3,4-dideoxyglucosone-3-ene (3,4-DGE) has been identified as the most toxic glucose degradation product in peritoneal dialysis fluids. Its role in renal pathophysiology has not been addressed. 3,4-DGE induces apoptosis in murine renal tubular epithelial cells in a dose- and time-dependent manner. Peak apoptosis is observed after 72 h of culture. The lethal concentration range is 25-50 micromol/l. 3,4-DGE results in Bax oligomerization, release of cytochrome c from mitochondria, activation of caspases-9 and -3, and Bid proteolysis. Apoptosis induced by 3,4-DGE is caspase dependent and could be prevented by the broad-spectrum caspase inhibitor zVAD-fmk (Z-Val-Ala-DL-Asp-fluoromethylketone) and by specific inhibitors of caspases-2, -8, and -9. However, caspase inhibition did not prevent eventual cell death. In contrast, antagonism of Bax by a Ku-70-derived peptide or antisense oligonucleotides prevented both apoptosis and cell death. In conclusion, 3,4-DGE promotes apoptosis of cultured renal parenchymal cells by a Bax- and caspase-dependent mechanism. A role for 3,4-DGE in diabetes complications in the kidney and in the modulation of residual renal function in peritoneal dialysis should be further explored.
Justo
Pilar
P
Division of Nephrology and Hypertension, Fundación Jiménez Díaz, Av Reyes Católicos 2, 28040 Madrid, Spain.
Sanz
Ana Belén
AB
Egido
Jesús
J
Ortiz
Alberto
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology*; D013997:Time Factors; D051028:bcl-2-Associated X Protein
C504711:3,4-dideoxyglucosone-3-ene; C494827:Bax protein, mouse; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D011753:Pyrones; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases