Diabetic complications are the leading cause of morbidity and mortality in diabetic patients. Oxidative stress and inflammation contributes to the loss of endothelial function and dysfunction of the vascular endothelium plays a major role in diabetic macrovascular and microvascular complications. We found that hydrogen sulfide can reduce the hyperglycemia-induced mitochondrial reactive oxygen species (ROS) production in endothelial cells and can prevent diabetic vascular dysfunction in aortic rings. However, it has not been possible to test the protective effect of hydrogen sulfide against long-term diabetic complications because of its short half-life.Novel slow-release hydrogen sulfide donors were generated that allow long-term hydrogen sulfide treatment. We now propose to test the protective effect of slow-release hydrogen sulfide donors against glucose-induced ROS generation and the development of diabetic long-term complications. We aim (1) to identify the most potent hydrogen sulfide donor compounds against hyperglycemia-induced ROS generation in endothelial cells (2) to test the efficacy of the lead compounds in human microvessels and (3) determine the efficacy of the most potent drug candidates against diabetic nephropathy in streptozotocin-induced diabetes (Type 1 diabetes model) and in db/db mice (Type 2 diabetes model).The mechanism of action of hydrogen sulfide against mitochondrial ROS generation suggests that slow-release hydrogen sulfide donors may be applicable against diabetic complications in humans. We expect that the proposed preclinical efficacy studies will initiate rapid clinical translation and these promising drugs will be used in human diabetic complications.