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The Journal of Neuroscience, April 18, 2007, 27(16):4472-4481; doi:10.1523/JNEUROSCI.5368-06.2007

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Cellular/Molecular
AKAP12 Regulates Human Blood–Retinal Barrier Formation by Downregulation of Hypoxia-Inducible Factor-1

Yoon Kyung Choi,^1 * Jeong Hun Kim,^2 * Woo Jean Kim,^4 * Hae Young Lee,¹ Jeong Ae Park,⁵ Sae-Won Lee,³ Dae-Kwan Yoon,¹ Hyun Ho Kim,¹ Hum Chung,² Young Suk Yu,² and Kyu-Won Kim¹

¹NeuroVascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea, ²Department of Ophthalmology, Seoul National University College of Medicine and Seoul Artificial Eye Center, ³Clinical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea, ⁴Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, and ⁵Department of Marine Biotechnology, College of Liberal Arts and Sciences, Anyang University, Incheon 417-833, Korea

Correspondence should be addressed to Dr. Kyu-Won Kim, NeuroVascular Coordination Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Email: qwonkim{at}plaza.snu.ac.kr

Many diseases of the eye such as retinoblastoma, diabetic retinopathy, and retinopathy of prematurity are associated with blood–retinal barrier (BRB) dysfunction. Identifying the factors that contribute to BRB formation during human eye development and maintenance could provide insights into such diseases. Here we show that A-kinase anchor protein 12 (AKAP12) induces BRB formation by increasing angiopoietin-1 and decreasing vascular endothelial growth factor (VEGF) levels in astrocytes. We reveal that AKAP12 downregulates the level of hypoxia-inducible factor-1 (HIF-1) protein by enhancing the interaction of HIF-1 with pVHL (von Hippel-Lindau tumor suppressor protein) and PHD2 (prolyl hydroxylase 2). Conditioned media from AKAP12-overexpressing astrocytes induced barriergenesis by upregulating the expression of tight junction proteins in human retina microvascular endothelial cells (HRMECs). Compared with the retina during BRB maturation, AKAP12 expression in retinoblastoma patient tissue was markedly reduced whereas that of VEGF was increased. These findings suggest that AKAP12 may induce BRB formation through antiangiogenesis and barriergenesis in the developing human eye and that defects in this mechanism can lead to a loss of tight junction proteins and contribute to the development of retinal pathologies such as retinoblastoma.

Key words: A-kinase anchor protein 12 (AKAP12); barriergenesis; blood–retinal barrier (BRB); hypoxia-inducible factor-1 ; retinoblastoma; retina

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Received Dec. 13, 2006; revised March 6, 2007; accepted March 12, 2007.

Correspondence should be addressed to Dr. Kyu-Won Kim, NeuroVascular Coordination Research Center, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Email: qwonkim{at}plaza.snu.ac.kr

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