Abstract

Kallistatin, a serine protease inhibitor (PI), inhibits kallikrein and kinin production and growth of human retinal capillary endothelial cells (RCEC). KS levels are decreased in retina, serum and vitreous of Db patients and in STZ-rats. The hypothesis formulated herein is that in diabetes, low KS leads to a weakened growth inhibition of EC in the retina, indirectly enhancing neo-vascularization.
Aims are: 1: identify the causes and mechanisms of low KS in DM by testing the effects of high glucose, insulin and hypoxia on KS production in RCEC and hepatocytes, 2: determine if KS effects on cell growth occur via the kallikrein-kinin system or through a KS-specific receptor or other growth factors. These effects will be tested in the presence or absence of a kinin receptor antagonist. KS-R will be defined on RCEC and the effect of KS on the expression of growth factors will be examined. 3: Retinal neovascularization, induced by hyperoxia in KS-transgenic mice will help determine whether overexpression of KS can reduce or prevent retinal NV in these mice. Thus, KS will be examined with respect to its effects as an endothelial growth inhibitor. The mechanisms of KS regulation may provide evidence of new pathogenic factors in DR.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012600-03
Application #
6179088
Study Section
Special Emphasis Panel (ZRG2-NMS (02))
Program Officer
Dudley, Peter A
Project Start
1998-09-30
Project End
2002-09-29
Budget Start
2000-09-30
Budget End
2002-09-29
Support Year
3
Fiscal Year
2000
Total Cost
$201,120
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425

  Publications

Gao, G; Shao, C; Zhang, S X et al. (2003) Kallikrein-binding protein inhibits retinal neovascularization and decreases vascular leakage. Diabetologia 46:689-98
Li, Yan; Roth, Steven; Laser, Martin et al. (2003) Retinal preconditioning and the induction of heat-shock protein 27. Invest Ophthalmol Vis Sci 44:1299-304
Jin, Ji; Guan, Ming; Sima, Jing et al. (2003) Decreased pigment epithelium-derived factor and increased vascular endothelial growth factor levels in pterygia. Cornea 22:473-7
Moiseyev, Gennadiy; Crouch, Rosalie K; Goletz, Patrice et al. (2003) Retinyl esters are the substrate for isomerohydrolase. Biochemistry 42:2229-38
Wu, Bill X; Chen, Yumei; Chen, Ying et al. (2002) Cloning and characterization of a novel all-trans retinol short-chain dehydrogenase/reductase from the RPE. Invest Ophthalmol Vis Sci 43:3365-72
Gao, Guoquan; Li, Yan; Gee, Stephen et al. (2002) Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium-derived factor: a possible mechanism for the anti-angiogenic activity of plasminogen kringle 5. J Biol Chem 277:9492-7
Znoiko, Sergey L; Crouch, Rosalie K; Moiseyev, Gennadiy et al. (2002) Identification of the RPE65 protein in mammalian cone photoreceptors. Invest Ophthalmol Vis Sci 43:1604-9
Gao, Guoquan; Li, Yan; Fant, James et al. (2002) Difference in ischemic regulation of vascular endothelial growth factor and pigment epithelium--derived factor in brown norway and sprague dawley rats contributing to different susceptibilities to retinal neovascularization. Diabetes 51:1218-25
Ma, J; Znoiko, S; Othersen, K L et al. (2001) A visual pigment expressed in both rod and cone photoreceptors. Neuron 32:451-61
Zhang, D; Kaufman, P L; Gao, G et al. (2001) Intravitreal injection of plasminogen kringle 5, an endogenous angiogenic inhibitor, arrests retinal neovascularization in rats. Diabetologia 44:757-65

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