title: 3,4-DGE is cytotoxic and decreases HSP27/HSPB1 in podocytes.
abstract: Hyperglycemia is the key driver of diabetic complications and increased concentrations of glucose degradation products. The study of peritoneal dialysis solution biocompatibility has highlighted the adverse biological effects of glucose degradation products. Recently, 3,4-dideoxyglucosone-3-ene (3,4-DGE) was identified as the most toxic glucose degradation product in peritoneal dialysis fluids. In addition, 3,4-DGE is present in high-fructose corn syrup, and its precursor 3-deoxyglucosone is increased in diabetes. The role of 3,4-DGE in glomerular injury had not been addressed. We studied the effects of 3,4-DGE on cultured human podocytes and in vivo in mice. 3,4-DGE induced apoptosis in podocytes in a dose- and time-dependent manner. 3,4-DGE promoted the release of cytochrome c from mitochondria and activation of caspase-3. While high glucose concentrations increased the levels of the podocyte intracellular antiapoptotic protein HSP27/HSPB1, 3,4-DGE decreased the expression of podocyte HSP27/HSPB1. Apoptosis induced by 3,4-DGE was caspase-dependent and could be prevented by the broad-spectrum caspase inhibitor zVAD-fmk. Antagonism of Bax by a Ku-70-derived peptide also prevented apoptosis. Intravenous administration of 3,4-DGE to healthy mice resulted in a decreased expression of HSP27/HSPB1 and caspase-3 activation in whole kidney and in podocytes in vivo. In conclusion, 3,4-DGE induces apoptotic cell death in cultured human podocytes, suggesting a potential role in glomerular injury resulting from metabolic disorders.
authors: Division of Nephrology, IdiPAZ, Paseo de la Castellana 260, 28046, Madrid, Spain, dolores.sanchez@idipaz.es.
authors: Maria Dolores
authors: MD
authors: Sanchez-Niño
authors: Jonay
authors: J
authors: Poveda
authors: Ana Belen
authors: AB
authors: Sanz
authors: Susana
authors: S
authors: Carrasco
authors: Marta
authors: M
authors: Ruiz-Ortega
authors: Rafael
authors: R
authors: Selgas
authors: Jesus
authors: J
authors: Egido
authors: Alberto
authors: A
authors: Ortiz
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism; D011753:Pyrones / Q000008:administration & dosage / Q000633:toxicity*; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C504711:3,4-dideoxyglucosone-3-ene; D000590:Amino Acid Chloromethyl Ketones; C494826:BAX protein, human; D061945:Caspase Inhibitors; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C486699:Hspb2 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D011753:Pyrones; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D053148:Caspase 3