This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Diabetic nephropathy is a major complication of diabetes and the leading cause of end-stage renal disease. The earliest morphological changes accompanying diabetic nephropathy are hemodynamic and structural changes in the renal glomerular and tubular compartments. At the cellular level, hypertrophy of themesangial cells is a hallmark of these early changes. Multiple lines of experimental evidence have revealed a prominent role for the interplay of the angiotensin II receptor type 1A (AT1 A) and p27Kip1 in diabetic mesangial cell hypertrophy. p27Kip1 is a cell cycle inhibitor that normally must be degraded to enableprogression from G1 to S phase. During hyperglycemia, p27Kip1 is inappropriately stabilized through signaling events from the AT1 A. An effector of the AT1A called RCBTB1 is required for the induction of cellular hypertrophy, but the function of RCBTB1 and how it contributes to hypertrophy following hyperglycemia are unknown. We have discovered that RCBTB1 is a component of the ubiquitin system and that the same domain of RCBTB1 that binds to the AT1A also interacts with UBE2E3, a ubiquitin conjugating enzyme. Our hypothesis is that UBE2E3 and RCBTB1 modulate the AT1A in a ubiquitin-dependent fashion to contribute to p27Kip1-dependent, mesangial cell hypertrophy. Our model system is rat mesangial cells, a well-characterized glomerular cell model that recapitulates the hypertrophy observed in diabeticnephropathy.
Our specific aims are: (1) to biochemically map the complexes formed between the AT1 A, RCBTB1, and UBE2E3, and (2) to determine if disrupting the expression/function of RCBTB1 and UBE2E3 alters p27Kip stabilization and cellular hypertrophy in response to high glucose. These studies will be done in tissue culture cells and complemented by studies in an STZ-rodent model of diabetic nephropathy. Kidneys from these animals will be analyzed histologically, immunohistologically, and biochemically for hypertrophy and p27Kip1 accumulation. To complement these aims, we will generate mice null for UBE2E3or RCBTB1. These animals will provide us with powerful tools to study UBE2E3 and RCBTB1 by genetic and physiological methods in validated animal models of diabetic disease. Collectively, the information learned from these studies may contribute to the rational design of new treatment options for diabetic nephropathy. Such therapies are desperately needed as the incidence of diabetes and renal failure escalate

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
1P20RR024215-01
Application #
7610817
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2007-09-15
Project End
2008-06-30
Budget Start
2007-09-15
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$282,993
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Short, Kevin R; Pratt, Lauren V; Teague, April M (2018) A single exercise session increases insulin sensitivity in normal weight and overweight/obese adolescents. Pediatr Diabetes :
Fu, Dongxu; Yu, Jeremy Y; Connell, Anna R et al. (2016) Beneficial Effects of Berberine on Oxidized LDL-Induced Cytotoxicity to Human Retinal Müller Cells. Invest Ophthalmol Vis Sci 57:3369-79
Fu, Dongxu; Yu, Jeremy Y; Yang, Shihe et al. (2016) Survival or death: a dual role for autophagy in stress-induced pericyte loss in diabetic retinopathy. Diabetologia 59:2251-61
Powell, Rebecca; Bubenshchikova, Ekaterina; Fukuyo, Yayoi et al. (2016) Wtip is required for proepicardial organ specification and cardiac left/right asymmetry in zebrafish. Mol Med Rep 14:2665-78
Basu, Arpita; Morris, Stacy; Nguyen, Angel et al. (2016) Effects of Dietary Strawberry Supplementation on Antioxidant Biomarkers in Obese Adults with Above Optimal Serum Lipids. J Nutr Metab 2016:3910630
Wang, Zhongxiao; Cheng, Rui; Lee, Kyungwon et al. (2015) Nanoparticle-mediated expression of a Wnt pathway inhibitor ameliorates ocular neovascularization. Arterioscler Thromb Vasc Biol 35:855-64
Tryggestad, Jeanie B; Wang, Joshua J; Zhang, Sarah X et al. (2015) Elevated plasma pigment epithelium-derived factor in children with type 2 diabetes mellitus is attributable to obesity. Pediatr Diabetes 16:600-5
Webb, Carol F; Ratliff, Michelle L; Powell, Rebecca et al. (2015) A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures. Biochem Biophys Res Commun 463:1334-1340
Du, Mei; Otalora, Laura; Martin, Ashley A et al. (2015) Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism. Mol Cell Biol 35:2771-89
Basu, Arpita; Yu, Jeremy Y; Jenkins, Alicia J et al. (2015) Trace elements as predictors of preeclampsia in type 1 diabetic pregnancy. Nutr Res 35:421-30

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