Abstract

In our previous work we have demonstrated that genetic factors controlling the production of bradykinin (BK) and nitric oxide (NO) influence greatly the development of renal complications in mice made diabetic with streptozotocin (STZ) or by the Akita diabetogenic C86Y mutation in Ins 2. We also showed that diabetic nephropathy and several indicators of senescence increase progressively in the order wildtype Specific aim 1 will determine the effect on diabetic complications of eliminating both BK receptors throughout the body, or in a tissue or cell specific manner;the effects of reducing oxidative stress in these mice will also be determined.
Specific aim 2 will investigate the relationship between glomerular damage and mtDNA mutations in eNOS -/- diabetic mice in which we have found that oxidative stress is paradoxically less than in eNOS +/+ diabetic mice.
Specific aim 3 will test the hypothesis that increasing the frequency of mtDNA mutations by introducing a proof reading defect into mitochondrial DNA polymerase gamma will exacerbate the complications in Akita diabetic mice even though oxidative stress is not further increased over that due to the diabetes alone.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK076131-05
Application #
7907809
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M1))
Program Officer
Ketchum, Christian J
Project Start
2006-09-30
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$327,266
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Matsuki, Kota; Hathaway, Catherine K; Lawrence, Marlon G et al. (2014) The role of transforming growth factor ?1 in the regulation of blood pressure. Curr Hypertens Rev 10:223-38
Li, Feng; Hagaman, John R; Kim, Hyung-Suk et al. (2012) eNOS deficiency acts through endothelin to aggravate sFlt-1-induced pre-eclampsia-like phenotype. J Am Soc Nephrol 23:652-60
Tomita, Hirofumi; Sanford, Ryan B; Smithies, Oliver et al. (2012) The kallikrein-kinin system in diabetic nephropathy. Kidney Int 81:733-44
Kayashima, Yukako; Smithies, Oliver; Kakoki, Masao (2012) The kallikrein-kinin system and oxidative stress. Curr Opin Nephrol Hypertens 21:92-6
Wang, Chih-Hong; Li, Feng; Hiller, Sylvia et al. (2011) A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy. Proc Natl Acad Sci U S A 108:2070-5
Li, F; Wang, C-H; Wang, J-G et al. (2010) Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet. J Thromb Haemost 8:2122-32
Wende, Adam R; Soto, Jamie; Olsen, Curtis D et al. (2010) Loss of bradykinin signaling does not accelerate the development of cardiac dysfunction in type 1 diabetic akita mice. Endocrinology 151:3536-42
Kakoki, Masao; Sullivan, Kelli A; Backus, Carey et al. (2010) Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice. Proc Natl Acad Sci U S A 107:10190-5
Kakoki, Masao; Smithies, Oliver (2009) The kallikrein-kinin system in health and in diseases of the kidney. Kidney Int 75:1019-30
Brosius 3rd, Frank C; Alpers, Charles E; Bottinger, Erwin P et al. (2009) Mouse models of diabetic nephropathy. J Am Soc Nephrol 20:2503-12