Protection of insulin-producing cells against toxicity of dexamethasone by catalase overexpression.
Pancreatic beta cells are very sensitive to reactive oxygen species (ROS) and this might play an important role in beta cell death in diabetes. Dexamethasone is a synthetic diabetogenic glucocorticoid, which impairs pancreatic beta cell function. Therefore we investigated the toxicity of dexamethasone in RINm5F insulin-producing cells and its dependence on the expression level of the antioxidant enzyme catalase, which inactivates hydrogen peroxide. This was correlated with oxidative stress and cell death. An increased generation of ROS was observed in dexamethasone-treated cells together with an increase in caspase-3 activity and apoptosis rate. Interestingly, exposure to dexamethasone increased the cytosolic superoxide dismutase Cu/ZnSOD protein expression and activity, whereas the mitochondrial MnSOD isoform was not affected by the glucocorticoid. Catalase overexpression in insulin-producing cells prevented all the cytotoxic effects of dexamethasone. In conclusion, dexamethasone-induced cell death in insulin-producing cells is ROS mediated. Increased levels of expression and activity of the Cu/ZnSOD might favor the generation of hydrogen peroxide in dexamethasone-treated cells. Increased ROS scavenging capacity in insulin-producing cells, through overexpression of catalase, prevents a deleterious increase in hydrogen peroxide generation and thus prevents dexamethasone-induced apoptosis.
Roma
Leticia P
LP
Department of Physiology and Biophysics, Institute of Biology, State University of Campinas, Campinas, SP 13.083-970, Brazil.
Bosqueiro
Jose R
JR
Cunha
Daniel A
DA
Carneiro
Everardo M
EM
Gurgul-Convey
Ewa
E
Lenzen
Sigurd
S
Boschero
Antonio C
AC
Souza
Kleber L A
KL
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002374:Catalase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002478:Cells, Cultured; D003907:Dexamethasone / Q000633:toxicity*; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D002374:Catalase; D053148:Caspase 3