The goal of this study is to develop low-dose radiation (LDR) as a new tool to prevent and treat diabetic nephropathy. Currently no effective preventive or therapeutic approaches are available to treat diabetic nephropathy, which is the most common cause of renal failure. We have been investigating the biological effects of LDR, including its hormesis and adaptive response, in vitro and in vivo. A major advantage of LDR is that it activates many genes in antioxidant and anti-inflammatory pathways, rather than just single protective gene, potentially making LDR a very potent and novel therapeutic approach. This was borne out by our preliminary studies that show that LDR at 25 mGy decreases diabetic nephropathy, by significantly reducing diabetes-induced renal oxidative damage and inflammation. Our latest preliminary data show up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and protein kinase B (also called Akt) phosphorylation in the kidney of diabetic mice, also exposed to LDR at 25 mGy. NRF2 is a transcription factor involved in expression of a broad range of protective genes. Therefore our central hypothesis is that exposure of diabetic animals to LDR can prevent and treat diabetic nephropathy by activation of many protective genes through stimulation of the Nrf2 pathway. This hypothesis will be tested through three specific Aims: (1) LDR at the optimal condition not only prevents, but also delay diabetic nephropathy;(2) the optimal LDR is safe for diabetic subjects;(3) the renal protection by the optimal LDR is predominantly mediated by up- regulating Nrf2-mediated multiple antioxidant components. The great advantage of LDR is that it offers a highly controllable, non-invasive method for eliciting endogenous, synergistic tissue protection and repair mechanisms. This innovative approach will be particularly valuable for the diabetic patient who already has significantly decreased renal function that increases the toxicity of invasive drugs. Therefore, this project will open a new avenue for the prevention and treatment of diabetic complications.

Public Health Relevance

The objective of this study is to apply low-dose radiation (LDR) as a new and non-invasive tool to prevent and treat diabetic nephropathy through stimulation of renal multiple protective mechanisms against oxidative damage and inflammation. We will firstly define the optimal condition of LDR to prevent and treat diabetic nephropathy with type 1 and type 2 diabetic mouse models, and then determine the safety for diabetic subjects to expose to LDR and underlying mechanisms for the renal protection from diabetes by LDR. This project represents a unique approach to apply LDR to activate multiple protective pathways unlike most currently- used drugs only working on a single pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK091338-01A1
Application #
8439792
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Flessner, Michael Francis
Project Start
2013-09-15
Project End
2015-08-31
Budget Start
2013-09-15
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$375,000
Indirect Cost
$125,000
Name
University of Louisville
Department
Pediatrics
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Zhao, Yuguang; Kong, Chuipeng; Chen, Xiao et al. (2016) Repetitive exposure to low-dose X-irradiation attenuates testicular apoptosis in type 2 diabetic rats, likely via Akt-mediated Nrf2 activation. Mol Cell Endocrinol 422:203-10
Wu, Hao; Kong, Lili; Tan, Yi et al. (2016) C66 ameliorates diabetic nephropathy in mice by both upregulating NRF2 function via increase in miR-200a and inhibiting miR-21. Diabetologia 59:1558-68
Jagadapillai, Rekha; Rane, Madhavi J; Lin, Xingyu et al. (2016) Diabetic Microvascular Disease and Pulmonary Fibrosis: The Contribution of Platelets and Systemic Inflammation. Int J Mol Sci 17:
Cheng, Yanli; Zhang, Jingjing; Guo, Weiying et al. (2016) Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy. Free Radic Biol Med 93:94-109
Barati, Michelle T; Powell, David W; Kechavarzi, Bobak D et al. (2016) Differential expression of endoplasmic reticulum stress-response proteins in different renal tubule subtypes of OVE26 diabetic mice. Cell Stress Chaperones 21:155-66
Zhang, Fangfang; Yu, Lechu; Lin, Xiufei et al. (2015) Minireview: Roles of Fibroblast Growth Factors 19 and 21 in Metabolic Regulation and Chronic Diseases. Mol Endocrinol 29:1400-13
Kong, Lili; Wu, Hao; Zhou, Wenhua et al. (2015) Sirtuin 1: A Target for Kidney Diseases. Mol Med 21:87-97
Wu, Hao; Kong, Lili; Cheng, Yanli et al. (2015) Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2. Free Radic Biol Med 89:431-42
Shao, Minglong; Yu, Lechu; Zhang, Fangfang et al. (2015) Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model. Am J Physiol Endocrinol Metab 309:E45-54
Xu, Zheng; Cai, Lu (2015) Diabetic cardiomyopathy: Role of epidermal growth factor receptor tyrosine kinase. J Mol Cell Cardiol 84:10-2

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