Tetrahydrobiopterin (BH(4)) Supplementation Prevents the Cardiorenal Effects of Diabetes in Mice by Reducing Oxidative Stress, Inflammation and Fibrosis

Background: The effects of diabetes on the cardiovascular system as well as in the kidney are profound, which include hypertrophy and fibrosis. Diabetes also induces oxidative stress, at least in part due to the uncoupling of nitric oxide synthase (NOS); this is a shift in NO production toward superoxide production due to reduced levels of the NOS cofactor tetrahydrobiopterin (BH(4)). With this in mind, we tested the hypothesis that BH(4) supplementation may prevent the development of diabetic cardiomyopathy and nephropathy. Methods: Diabetes was induced in Balb/c mice with streptozotocin. Then, diabetic mice were divided into two groups: one group provided with BH(4) (sapropterin) in drinking water (daily doses of 15 mg/kg/day, during eight weeks) and the other that received only water. A third group of normoglycemic mice that received only water were used as the control. Results: Cardiac levels of BH(4) were increased in mice treated with BH(4) (p = 0.0019). Diabetes induced cardiac hypertrophy, which was prevented in the group that received BH(4) (p < 0.05). In addition, hypertrophy was evaluated as cardiomyocyte cross-sectional area. This was reduced in diabetic mice that received BH(4) (p = 0.0012). Diabetes induced cardiac interstitial fibrosis that was reduced in mice that received BH(4) treatment (p < 0.05). We also evaluated in the kidney the impact of BH(4) treatment on glomerular morphology. Diabetes induced glomerular hypertrophy compared with normoglycemic mice and was prevented by BH(4) treatment. In addition, diabetic mice presented glomerular fibrosis, which was prevented in mice that received BH(4). Conclusions: These results suggest that chronic treatment with BH(4) in mice ameliorates the cardiorenal effects of diabetes,(,) probably by restoring the nitroso–redox balance. This offers a possible new alternative to explore a BH(4)-based treatment for the organ damage caused by diabetes.