Thiol-related genes in diabetic complications: a novel protective role for endogenous thioredoxin 2.

OBJECTIVE

Our laboratory and others have found that deficiencies in cellular thiols may be importantly involved in the development of diabetic complications. However, the role for specific thiol-related genes in diabetic complications is unclear.

METHODS AND RESULTS

We began the present study by systematically determining the expression level of 11 thiol-related genes in three tissues from rats with streptozotocin-induced diabetes. Several thiol-related genes were found to exhibit diabetes-associated, time-dependent differential expression. Thioredoxin 2, a mitochondrion-specific thioredoxin whose role in diabetes was unknown, was suppressed in the aorta from rats with two weeks of diabetes. When thioredoxin 2 expression in human umbilical vein endothelial cells was knocked-down by small interfering RNA, high-ambient glucose-elicited substantial injurious effects (n=5 to 9, P<0.05), including increases in cytosolic cytochrome c (by 2.2+/-0.6-fold), lipid peroxidation (by 40+/-8%), fibronectin expression (by 35+/-7%), and oxidized glutathione, and decreases in endothelial nitric oxide synthase expression (by 79+/-15%), basal accumulation of nitrite/nitrate (by 68+/-16%), total free thiols (by 42+/-8%), and glutathione (by 6+/-1%). In the absence of thioredoxin 2 knockdown, high-ambient glucose did not have significant effects on any of these measurements. The effect of thioredoxin 2 knockdown appeared to be associated with increases in glucose consumption and glucose transporter 1 expression.

CONCLUSIONS

These results provided the first expression profile of thiol-related genes in a model of diabetes and demonstrated a novel role for endogenous thioredoxin 2 in protecting cells against high ambient glucose.