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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK094930-03S1
Application #
8816879
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2012-04-01
Project End
2017-06-30
Budget Start
2014-09-15
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Hershey
State
PA
Country
United States
Zip Code
17033
You, Hanning; Gao, Ting; Raup-Konsavage, Wesley M et al. (2016) Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice. Kidney Int :
You, Hanning; Gao, Ting; Cooper, Timothy K et al. (2015) Arginase inhibition: a new treatment for preventing progression of established diabetic nephropathy. Am J Physiol Renal Physiol 309:F447-55
Awad, Alaa S; You, Hanning; Gao, Ting et al. (2015) Macrophage-derived tumor necrosis factor-α mediates diabetic renal injury. Kidney Int 88:722-33
Sun, Yuan-Wan; El-Bayoumy, Karam; Aliaga, Cesar et al. (2015) Tissue Distribution, Excretion and Pharmacokinetics of the Environmental Pollutant Dibenzo[def,p]chrysene in Mice. Chem Res Toxicol 28:1427-33
Awad, Alaa S; You, Hanning; Gao, Ting et al. (2015) Delayed Treatment with a Small Pigment Epithelium Derived Factor (PEDF) Peptide Prevents the Progression of Diabetic Renal Injury. PLoS One 10:e0133777
You, Hanning; Gao, Ting; Cooper, Timothy K et al. (2014) Diabetic nephropathy is resistant to oral L-arginine or L-citrulline supplementation. Am J Physiol Renal Physiol 307:F1292-301
Awad, Alaa S; Gao, Ting; Gvritishvili, Anzor et al. (2013) Protective role of small pigment epithelium-derived factor (PEDF) peptide in diabetic renal injury. Am J Physiol Renal Physiol 305:F891-900
You, Hanning; Gao, Ting; Cooper, Timothy K et al. (2013) Arginase inhibition mediates renal tissue protection in diabetic nephropathy by a nitric oxide synthase 3-dependent mechanism. Kidney Int 84:1189-97
You, Hanning; Gao, Ting; Cooper, Timothy K et al. (2013) Macrophages directly mediate diabetic renal injury. Am J Physiol Renal Physiol 305:F1719-27
Abdel-Rahman, Emaad M; Alhamad, Tarek; Reeves, W Brian et al. (2012) Management of Diabetic Nephropathy in the Elderly: Special Considerations. J Nephrol Ther 2:

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