Diacylglycerol kinase (DGK) inhibitor II (R59949) could suppress retinal neovascularization and protect retinal astrocytes in an oxygen-induced retinopathy model.

Abstract

Hypoxia-inducible factors (HIF) play a fundamental role in retinal neovascularization (NV) induced by low oxygen tension. In the presence of oxygen, the HIF-α subunit becomes hydroxylated at specific prolyl residues by prolyl hydroxylases (PHD), which triggers HIF-α for degradation. In our present study, we examined the effect of R59949, the diacylglycerol kinase (DGK) inhibitor II, on the retinal NV and its potential mechanism in an oxygen-induced retinopathy (OIR) model. OIR model was induced by exposure of hyperoxia (75 % oxygen) to C57BL/6J mice from postnatal day 7 (P7) to P12 and then returned to room air. By intraperitoneal injection once a day (10 μg/g/day) from P12 to P17, R59949 not only effectively prevented pathologic NV but also preserved the astrocyte morphology. Furthermore, the expression of PHD-2 was upregulated and HIF-1α and vascular endothelial growth factor (VEGF) were downregulated in the retina of OIR mice following R59949 treatment. These findings suggested a potential possibility that R59949 suppressed retinal neovascular pathophysiology via PHD2/HIF-1α/VEGF pathway.

• Authors: Lu Yang, Yue Xu, Weihua Li, Boyu Yang, Shanshan Yu, Huanjiao Zhou, Cheng Yang, Fan Xu, Jun Wang, Yi Gao, Yongsheng Huang, Lin Lu, Xiaoling Liang
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 56 Issue 1 Pg. 78-88 (May 2015) ISSN: 1559-1166 [Electronic] United States
• PMID: 25451596 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Piperidines
• Quinazolinones
• Vascular Endothelial Growth Factor A
• R 59949
• Egln1 protein, mouse
• Hypoxia-Inducible Factor-Proline Dioxygenases
• Diacylglycerol Kinase

Topics

• Animals
• Astrocytes (drug effects, metabolism)
• Diacylglycerol Kinase (antagonists & inhibitors)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Neovascularization, Pathologic (drug therapy)
• Piperidines (pharmacology, therapeutic use)
• Quinazolinones (pharmacology, therapeutic use)
• Retina (drug effects, pathology)
• Retinal Vessels (drug effects, pathology)
• Retinopathy of Prematurity (drug therapy)
• Vascular Endothelial Growth Factor A (genetics, metabolism)