The prevalence of diagnosed and undiagnosed diabetes in the US is progressively increasing from 7.8% in 2007, 14.5% in 2010 and expected to rise to between 24.7% and 32.8% in 2050. Diabetic nephropathy (DN) remains an important and unresolved complication of diabetes. It has become evident that endothelial cell dysfunction is a central pathophysiological mechanism contributing to diabetes and DN. Growing evidence from our work and others suggests that dramatic alterations in arginine metabolism occur during endothelial injury in response to changes in the activity and/or expression of nitric oxide synthases (NOS) and/or arginases. Arginase-2 is constitutively expressed and regulated in the kidney, but not arginase-1. Our recent work demonstrates that arginase inhibition mediates renal tissue protection in DN via an eNOS-dependent mechanism. Therefore, we hypothesize that a selective inhibitor of arginase-2 will prove to be an optimal drug for protecting against diabetic nephropathy. Such a selective agent would be a valuable adjunct to blood glucose control in mitigating this important unmet medical need.
Aim 1 : Modify our novel lead compound ASR-133 to render it more arginase-2 selective and potent.
Aim 2 : In vitro assessment of pharmacotherapeutic potential of arginase inhibitors. Identification of an arginase-2 selective inhibitor would provide a potentially important pre-therapeutic lead for the treatment of diabetic renal complications and may provide a new therapeutic approach to the management of DN.
Currently, the only effective approaches to reduce the progression of diabetic nephropathy are to control the blood glucose and blood pressure levels. Our current hypothesis is that the selective inhibition of arginase-2 will serve to protect the kidney from diabetic nephropathy;however, no arginase-2 specific inhibitors currently exist. Therefore, the current study will develop arginase-2 selective inhibitors to provide a new therapeutic approach to the development and progression of diabetic nephropathy.
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