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    Targeting survival pathway for future therapeutics for diabetic retinopathy

    XBP1 shown to have essential role in retinal endothelial cell survival

    XBP1 shown to have essential role in retinal endothelial cell survival

    Take-home message: The transcription factor XBP1 appears to have an expanding role in endothelial cell survival and retinal vascular degeneration as it relates to aging and diabetes.

    Reviewed by Sarah X. Zhang, MD

    Buffalo, NY—The transcription factor X-box binding protein 1 (XBP1) may one day be a new therapeutic target to help prevent vascular damage in diabetic retinopathy, said Sarah X. Zhang, MD.

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    Research led by Dr. Zhang and co-authors have found that XBP1 has an important role in retinal endothelial cell survival. Dr. Zhang is associate professor, Department of Ophthalmology, Jacobs School of Medicine and Biomedical Sciences, The State University of New York at Buffalo, New York.

    The finding builds on previous research from Dr. Zhang’s laboratory, which has focused on the role of retinal endothelial cells and signaling pathways of the unfolded protein response (UPR) in diabetic eye diseases. Studies by the Zhang group and others suggest that diabetes activates the UPR by inducing endoplasmic reticulum stress in retinal endothelial cells and the activation of UPR pathways has been implicated in retinal inflammation and vascular leakage at early stages of the disease.

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    Progressive loss of retinal endothelial cells is a central event in the pathogenesis of diabetic retinopathy, according to researchers. Many detrimental factors contribute to the endothelial cell loss in diabetic retina, however, the exact mechanism remains unclear.

    In this project, Dr. Zhang and colleagues investigated whether XBP1, a major transcription factor of the UPR, plays a role in endothelial cell survival during diabetes.

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    In the in vitro study using primary human retinal endothelial cells, researchers found that the blockade of XBP1 activation by a pharmacological inhibitor exacerbated endoplasmic reticulum stress- or high glucose-induced apoptosis. Conditional deletion of XBP1 in brain microvascular endothelial cells (BMECs) led to impaired cell proliferation and migration as well as increased apoptosis under high-glucose conditions. These changes had a major reversal when treated with adenoviral vectors expressing active XBP1.

    “These findings are exciting, as they suggest a vital role of XBP1 in endothelial cell survival under stress conditions such as diabetes,” Dr. Zhang said.

    Showing promise


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