Diabetic nephropathy represents the primary cause of end stage renal disease (ESRD) in the US, underscoring the need for innovative therapies for preventing its progression. We are interested in understanding the cellular and molecular mechanisms that govern mitochondrial dysfunction in the diabetic milieu with the expectation that understanding of these processes will expose potential disease mechanisms and therapeutic targets in diabetic nephropathy. The present proposal is based on our recent published observation, indicating that ROCK1-mediated mitochondrial fragmentation is essential for prompting mitochondrial dysfunction in podocytes and glomerular endothelial cells in the diabetic milieu. A detailed understanding of mechanisms that govern mitochondrial fission in the kidney remains incomplete and therapeutic targets based on these mechanisms do not exist. Because dynamin-related protein-1 (Drp1) is an integral part in regulating mitochondrial fission, we have focused on investigating the functions of ROCK1 on Drp1 translocation to the mitochondria resulting in mitochondrial fragmentation and cell apoptosis. We have been guided by our recent published observations that ROCK1 mediates high glucose-induced mitochondrial fragmentation by promoting Drp1 recruitment to the mitochondria. Deletion of ROCK1 in db/db diabetic mice prevented mitochondrial fission, whereas podocyte-specific constitutively active (cA)-ROCK1 mice exhibited increased mitochondrial fission. Importantly, we found that ROCK1 triggers mitochondrial fission by phosphorylating Drp1 at serine 600 residue. These findings provide compelling initial evidence into the unexpected role of ROCK1 in a signaling cascade that regulates mitochondrial dynamics, and represents a therapeutic target that might be useful in preventing diabetic kidney disease. Given these results and additional preliminary data presented in this application, this project will address the hypothesis that phosphorylation of Drp1 is a key feature of mitochondria dysfunction in diabetic nephropathy. The results of this study will provide important new insights into the role of mitochondrial morphology in the development of diabetic nephropathy, and may lead to novel therapeutic targets for the future treatment of diabetic kidney disease.

Public Health Relevance

Diabetes is the most common metabolic disease in the world and the leading cause of end stage renal disease. The focus of this proposal is to examine the role of Rho- associated coiled-coil containing protein kinase 1 (ROCK1) on mitochondrial dysfunction in experimental models of diabetic kidney disease. The results of this study will provide important new insights into the role of mitochondrial morphology in the development of diabetic nephropathy, and may lead to novel therapeutic targets for the future treatment of diabetic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK078900-07
Application #
8662961
Study Section
Special Emphasis Panel (ZRG1-DKUS-A (04))
Program Officer
Rys-Sikora, Krystyna E
Project Start
2007-07-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
7
Fiscal Year
2014
Total Cost
$348,000
Indirect Cost
$130,500
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Badal, Shawn S; Danesh, Farhad R (2014) New insights into molecular mechanisms of diabetic kidney disease. Am J Kidney Dis 63:S63-83
Long, Jianyin; Badal, Shawn S; Wang, Yin et al. (2013) MicroRNA-22 is a master regulator of bone morphogenetic protein-7/6 homeostasis in the kidney. J Biol Chem 288:36202-14
Wang, Wenjian; Wang, Yin; Long, Jianyin et al. (2012) Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab 15:186-200
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Long, Jianyin; Wang, Yin; Wang, Wenjian et al. (2011) MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy. J Biol Chem 286:11837-48
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