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A novel role for endogenous thioredoxin 2 in protecting cells against the injurious effect of high ambient glucose

Our laboratory (Physiol Genomics 17: 271, 2004; 21: 222, 2005) and others have found that cellular thiols may be importantly involved in the development of diabetic complications. However, the specific role of each thiol‐related gene in diabetic complications is unclear. We began the present study by systematically determining the expression level of 11 thiol‐related genes in several tissues from rats with streptozotocin‐induced diabetes with or without the insulin treatment. Several genes were found to exhibit diabetes‐associated differential expression, including a suppression of thioredoxin 2, a mitochondrial protein, in the aorta. When thioredoxin 2 expression in human umbilical vein endothelial cells was silenced by small interfering RNA, high ambient glucose elicited substantial injurious effects (n=6–9, P<0.05), including decreases in endothelial nitric oxide synthase expression (by 79 ± 15%), basal accumulation of nitrite/nitrate (by 68 ± 16%), and cellular thiols (by 42 ± 8%), and increases in cytosolic cytochrome c (by 2.2 ± 0.6 fold), lipid peroxidation (by 40 ± 8%), and fibronectin expression (by 35 ± 7%). In the presence of intact thioredoxin 2, high ambient glucose did not have significant effects on any of the above measurements except a modest reduction of cellular thiols. Silencing of thioredoxin 2 appeared to be associated with increases in glucose consumption and glucose transporter 1 expression. These results demonstrated a novel role for endogenous thioredoxin 2 in protecting cells against high ambient glucose, providing new insights into the role of specific thiol‐related genes in diabetic complications. (NIH R01 HL077263)