Involvement of the Rho/Rho Kinase Signaling Pathway in Platelet-Derived Growth Factor BB-induced Vascular Endothelial Growth Factor Expression in Diabetic Rat Retina

Abstract

To examine the role played by the Rho/Rho kinase pathway in the platelet-derived growth factor BB (PDGF-BB)-induced expression of vascular endothelial growth factor (VEGF) in the diabetic rat retina. Male Sprague-Dawley rats were made diabetic by a single intraperitoneal injection of streptozotocin. Diabetic rats and PDGF-BB-exposed primary cultured porcine retinal pericyte cells (PRPCs) were treated with fluvastatin, an HMG-CoA reductase inhibitor, and fasudil, a selective Rho kinase inhibitor. The retinal expression of VEGF was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The mRNA expression of VEGF and the activation of Rho A were studied by Northern and Western blot analyses. RT-PCR showed that in rats that were diabetic for 4 weeks VEGF mRNA expression levels were 1.8-fold those in control rats. This enhanced expression was blocked by treatment with fluvastatin or fasudil. Exposure of PRPCs to PDGF-BB increased their VEGF mRNA expression threefold, and fluvastatin suppressed this effect. Fluvastatin also suppressed the PDGF-BB-induced activation of Rho GTPase in PRPCs. The Rho/Rho kinase pathway may be involved in the upregulation of VEGF expression in the diabetic retina, suggesting that fasudil might be useful for the prevention of diabetic retinopathy.