Selective loss of pericytes is an early pathological change in diabetic retinopathy. The loss of pericytes may impair the integrity of the retinal microvasculature, leading to breakdown of the blood-ocular barrier. We have previously found that high glucose reduces pericyte viability and also decreases phosphatidylinositol bisphosphate (PIP2) levels. We hypothesize that the reduction in pericyte viability by high glucose is mediated through the inositol phospholipid-signal transduction process. In this application we propose to study the biochemical mechanisms by which this occurs. Activated sorbitol pathway and decreased myo-inositol content induced by high glucose may alter cell signal transduction through reduced PIP2 levels. We propose to study pericyte metabolism under high glucose conditions to determine what leads to the decrease in PIP2. Gp, a member of the family of GTP-binding proteins, couples external signal receptors to the enzyme phosphoinositidase (PIase) which catalyzes PIP2 hydrolysis. Therefore, Gp levels and PIase activities will be determined. The products of PIP2 hydrolysis and other signal messengers (IP3, DG, cAMP, intracellular Ca+2 and Protein kinase C and A) will also be measured. The incorporation of tritium-labelled thymidine, an index of cell proliferation, will be used to correlate components of the inositol phospholipid signal system with pericyte viability. In the proposed studies, the supplementation of myoinositol, insulin or aldose reductase inhibitors to pericytes grown in high glucose medium will be used as in vitro """"""""therapy"""""""" to attempt to correct the reduced rate of pericyte proliferation. The results of these investigations may lead to a better understanding of the pathogenesis of diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY006563-04
Application #
3262869
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1986-08-01
Project End
1993-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Hahnemann University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Li, W; Liu, X (1994) Interaction between phosphoinositide-phospholipase C and phosphatidylcholine-phospholipase D in plasma membranes of retinal capillary pericytes. Ophthalmic Res 26:189-95
Li, W; Wang, W; Liu, X (1994) Comparative study of high-glucose effect on phosphatidylcholine hydrolysis of cultured retinal capillary pericytes and endothelial cells. Biochim Biophys Acta 1222:339-47
Li, W; Liu, X; Yanoff, M (1994) Different responses of choriocapillary endothelial cells and retinal capillary endothelial cells to mitogenic and vasoactive factors. Chin Med Sci J 9:96-9
Li, W; Tao, L; Yanoff, M (1994) Agonist-induced phosphatidylinositide breakdown and mitogenesis in retinal capillary pericytes. Ophthalmic Res 26:36-40
Liu, X; Li, W (1993) Isolation, culture and characterization of bovine choriocapillary endothelial cells. Exp Eye Res 57:37-44
Tao, L; Li, W (1992) Rapid and sensitive anion-exchange high-performance liquid chromatographic determination of radiolabeled inositol phosphates and inositol trisphosphate isomers in cellular systems. J Chromatogr 607:19-24
Li, W; Ye, X; Tao, L et al. (1992) Comparison and characterization of retinal pericytes and retinal pigment epithelial cells on subcellular IP3-sensitive Ca2+ pools. Cell Prolif 25:651-62
Li, W Y; Zhou, Q; Qin, M et al. (1991) Reduced absolute rate of myo-inositol biosynthesis of cultured bovine retinal capillary pericytes in high glucose. Exp Eye Res 52:569-73
Li, W Y; Zhou, Q; Tang, L et al. (1990) Intramural pericyte degeneration in early diabetic retinopathy study in vitro. Chin Med J (Engl) 103:7-13
Li, W Y; Tang, L; Zhou, Q et al. (1989) DNA-synthesis regulation and correlation with inositol trisphosphate levels in cultured bovine retinal capillary pericytes. Exp Eye Res 49:677-83

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