ARF6 Plays Key Role in Diabetes-Induced Blindness

Graphic- ARF6 Plays Key Role in Diabetes-Induced Blindness
In diabetic macular edema, ARF6 regulates the VEGF signaling pathway at two critical points (circled in red): co-receptor binding and receptor internalization.

Diabetic macular edema, the most common cause of blindness in the United States, is triggered by inflammation, the growth of new blood vessels, and fluid leakage from blood vessels into the retina. Vascular endothelial growth factor (VEGF) is a protein known to play a major role in all of those processes. However, existing anti-VEGF treatments often fail to achieve adequate effects. 

University of Utah Health researcher Weiquan Zhu, PhD, and colleagues identified a protein, known as ARF6, which regulates the effects of VEGF by maintaining and amplifying its receptor signaling, thus stimulating a series of cascading responses that lead to diabetic retinal edema. In mouse and rat studies, when ARF6 was eliminated through genetic manipulation in blood-vessel endothelial cells or suppressed through injection of an inhibitory compound, NAV-2729, the eye was protected from fluid leakage and damage. 

These results have important implications not only for the treatment of diabetic macular edema and other related eye diseases, but also for other disorders that involve VEGF receptor activation, such as acute and chronic inflammation and cancer.

References:

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Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy. Zhu W, Shi DS, Winter JM, Rich BE, Tong Z, Sorensen LK, Zhao H, Huang Y, Tai Z, Mleynek TM, Yoo JH, Dunn C, Ling J, Bergquist JA, Richards JR, Jiang A, Lesniewski LA, Hartnett ME, Ward DM, Mueller AL, Ostanin K, Thomas KR, Odelberg SJ, Li DY. J Clin Invest. 2017 Dec 1;127(12):4569-4582.

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U of U Health Key Faculty Collaborators

Mary Elizabeth Hartnett, MD, PhD
Diane M Ward, PhD
Lisa A. Lesniewski, PhD