IOVS Journal of Clinical Investigation
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Originally published In Press as doi:10.1167/iovs.07-1643 on March 24, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:3216-3223.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1643
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Role of the Polyol Pathway in High Glucose–Induced Apoptosis of Retinal Pericytes and Proliferation of Endothelial Cells

Yoshihiro Takamura, Takeshi Tomomatsu, Eri Kubo, Syousai Tsuzuki, and Yoshio Akagi

From the Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

PURPOSE. The selective degeneration of pericytes and the proliferation of endothelial cells (ECs) appear to be associated with microaneurysm formation, an initial deficit in the early stage of diabetic retinopathy. The preventive effect of aldose reductase (AR) inhibitor (ARI) for high glucose–induced pericyte loss and EC growth was investigated.

METHODS. The effect of high glucose (30 mM) exposure in the presence or absence of ARI for the cell growth of porcine pericytes and ECs was examined with the use of an in vitro coculture system to mimic the interaction between pericytes and ECs. To determine the role of transforming growth factor (TGF)-β, its amount in culture media was measured, and the effects of the treatment of TGF-β or neutralizing antibody on EC growth were examined.

RESULTS. Abundant expression of AR and increased levels of polyol and apoptosis induced by high glucose were observed in pericytes, but not in ECs. ECs overexpressing AR cultured in high-glucose medium showed decreased cell viability. The growth-inhibitory effect of ECs on coculture with pericytes was attenuated by exposure to a high glucose concentration. Biochemical assays disclosed that the levels of active TGF-β in media were linked to EC growth. Supply of active TGF-β to coculture medium containing 30 mM D-glucose restored the inhibitory activity on EC growth.

CONCLUSIONS. ARI rescued pericytes from high glucose–induced apoptosis and maintained the levels of TGF-β, resulting in the prevention of cocultured EC growth.






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