Sanchez-Niño Maria Dolores, Poveda Jonay, Sanz Ana Belen, Carrasco Susana, Ruiz-Ortega Marta, Selgas Rafael, Egido Jesus, Ortiz Alberto
Division of Nephrology, IdiPAZ, Paseo de la Castellana 260, 28046, Madrid, Spain,
Arch Toxicol. 2014 Mar;88(3):597-608. doi: 10.1007/s00204-013-1181-7. Epub 2013 Dec 15.
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.
高血糖是糖尿病并发症及葡萄糖降解产物浓度升高的关键驱动因素。腹膜透析液生物相容性的研究凸显了葡萄糖降解产物的不良生物学效应。最近，3,4 - 二脱氧葡萄糖烯（3,4 - DGE）被确定为腹膜透析液中毒性最强的葡萄糖降解产物。此外，3,4 - DGE存在于高果糖玉米糖浆中，其前体3 - 脱氧葡萄糖在糖尿病患者体内含量升高。3,4 - DGE在肾小球损伤中的作用尚未得到探讨。我们研究了3,4 - DGE对培养的人足细胞以及小鼠体内的影响。3,4 - DGE以剂量和时间依赖性方式诱导足细胞凋亡。3,4 - DGE促进细胞色素c从线粒体释放并激活caspase - 3。虽然高糖浓度会增加足细胞内抗凋亡蛋白HSP27/HSPB1的水平，但3,4 - DGE会降低足细胞HSP27/HSPB1的表达。3,4 - DGE诱导的凋亡依赖于caspase，可被广谱caspase抑制剂zVAD - fmk阻止。Ku - 70衍生肽对Bax的拮抗作用也可防止凋亡。对健康小鼠静脉注射3,4 - DGE会导致体内全肾及足细胞中HSPB1表达降低和caspase - 3激活。总之，3,4 - DGE诱导培养的人足细胞发生凋亡性细胞死亡，提示其在代谢紊乱所致肾小球损伤中可能发挥作用。
