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Nuclear receptor ROR? regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation.


ABSTRACT: Pathologic ocular angiogenesis is a leading cause of blindness, influenced by both dysregulated lipid metabolism and inflammation. Retinoic-acid-receptor-related orphan receptor alpha (ROR?) is a lipid-sensing nuclear receptor with diverse biologic function including regulation of lipid metabolism and inflammation; however, its role in pathologic retinal angiogenesis remains poorly understood. Using a mouse model of oxygen-induced proliferative retinopathy, we showed that ROR? expression was significantly increased and genetic deficiency of ROR? substantially suppressed pathologic retinal neovascularization. Loss of ROR? led to decreased levels of proinflammatory cytokines and increased levels of antiinflammatory cytokines in retinopathy. ROR? directly suppressed the gene transcription of suppressors of cytokine signaling 3 (SOCS3), a critical negative regulator of inflammation. Inhibition of SOCS3 abolished the antiinflammatory and vasoprotective effects of ROR? deficiency in vitro and in vivo. Moreover, treatment with a ROR? inverse agonist SR1001 effectively protected against pathologic neovascularization in both oxygen-induced retinopathy and another angiogenic model of very-low-density lipoprotein receptor (Vldlr)-deficient (Vldlr (-/-) ) mice with spontaneous subretinal neovascularization, whereas a ROR? agonist worsened oxygen-induced retinopathy. Our data demonstrate that ROR? is a novel regulator of pathologic retinal neovascularization, and ROR? inhibition may represent a new way to treat ocular neovascularization.

SUBMITTER: Sun Y 

PROVIDER: S-EPMC4547221 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation.

Sun Ye Y   Liu Chi-Hsiu CH   SanGiovanni John Paul JP   Evans Lucy P LP   Tian Katherine T KT   Zhang Bing B   Stahl Andreas A   Pu William T WT   Kamenecka Theodore M TM   Solt Laura A LA   Chen Jing J  

Proceedings of the National Academy of Sciences of the United States of America 20150804 33


Pathologic ocular angiogenesis is a leading cause of blindness, influenced by both dysregulated lipid metabolism and inflammation. Retinoic-acid-receptor-related orphan receptor alpha (RORα) is a lipid-sensing nuclear receptor with diverse biologic function including regulation of lipid metabolism and inflammation; however, its role in pathologic retinal angiogenesis remains poorly understood. Using a mouse model of oxygen-induced proliferative retinopathy, we showed that RORα expression was sig  ...[more]

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