Targeting survival pathway for future therapeutics for diabetic retinopathy

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

To explore the potential mechanism, researchers measured several important factors associated with apoptosis, including endoplasmic reticulum stress, mitochondrial damage, and reactive oxygen species generation. They found that XBP1-negative BMECs manifested reduced mitochondria membrane potential, increased superoxide generation and lipid peroxidation, decreased glutathione peroxidase (Gpx) activity, and reduced level of glutathione.

“This could imply a role of XBP1 in regulation of mitochondria’s ability to remove the toxic reactive oxygen species,” Dr. Zhang said.

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Coincident with the results from the in vitro study, researchers found that the 15-month-old XBP1 knockout mice (mice lacking XBP1 gene in endothelial cells) and the diabetic XBP1 knockout mice had increased acellular capillary formation (indicating loss of cells in small blood vessels), a reduced number of endothelial cells, and less vascular density in their retinas when compared with corresponding wild type controls.

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“These findings suggest an essential role of XBP1 in retinal endothelial cell survival likely through coordinating the endoplasmic reticulum and mitochondrial responses to cell stress,” the researchers concluded. “Enhancing the function of XBP1 and its downstream effectors in the anti-apoptotic pathways may therefore provide novel therapeutic approaches to the prevention of vascular damage in diabetic retinopathy and age-related retinal disease.”

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Dr. Zhang and fellow researchers are continuing to look at the mechanisms of XBP1, how it regulates endothelial cell survival and function, and whether this is through modulation of mitochondrial and endoplasmic reticulum activities. They are also evaluating whether enhancing the survival pathways regulated by XBP1 would provide protective effect against endothelial cell and vascular damage in diabetic retinas.

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Sarah X. Zhang, MD

E: xzhang38@buffalo.edu
This article was adapted from Dr. Zhang’s presentation at the 2016 meeting of the Association for Research and Vision in Ophthalmology. Dr. Zhang did not indicate any financial interest in the subject matter.