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Conditional Knockdown of Tubedown-1 in Endothelial Cells Leads to Neovascular Retinopathy

¹From the Division of Basic Medical Sciences, Department of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada; and the ²Smith Kettlewell Eye Research Institute, San Francisco, California.

PURPOSE. Identification of novel proteins involved in retinal neovascularization may facilitate new and more effective molecular-based treatments for proliferative retinopathy. Tubedown-1 (Tbdn-1) is a novel protein that shows homology to the yeast acetyltransferase subunit NAT1 and copurifies with an acetyltransferase activity. Tbdn-1 is expressed in normal retinal endothelium but is specifically suppressed in retinal endothelial cells from patients with proliferative diabetic retinopathy. The purpose of this study was to investigate the importance of Tbdn-1 expression in retinal blood vessels in vivo.

METHODS. A bitransgenic mouse model that enables conditional knockdown of Tbdn-1 specifically in endothelial cells was produced and studied using molecular, histologic, and immunohistochemical techniques and morphometric analysis.

RESULTS. Tbdn-1–suppressed mice exhibited retinal and choroidal neovascularization with intra- and preretinal fibrovascular lesions similar to human proliferative retinopathies. Retinal lesions observed in Tbdn-1–suppressed mice increased in severity with prolonged suppression of Tbdn-1. In comparison to normal retina, the retinal lesions displayed alterations in the basement membrane of blood vessels and in the distribution of glial and myofibroblastic cells. Moreover, the pathologic consequences of Tbdn-1 knockdown in endothelium were restricted to the retina and the choroid.

CONCLUSIONS. These results indicate that the maintenance of Tbdn-1 expression is important for retinal blood vessel homeostasis and for controlling retinal neovascularization in adults. Restoration of Tbdn-1 protein expression and/or activity may provide a novel approach for treating proliferative retinopathies.

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