June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
EET Blockade: A New Method to Optimize AT1 Blockade in the Treatment of Diabetic Retinopathy
Author Affiliations & Notes
  • Mohamed Al-Sayed Al-Shabrawey
    Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, United States
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
  • Amany M Tawfik
    Eye Research Institute, Oakland University, Rochester, Michigan, United States
    Eye Research Center, Oakland University William Beaumont School of Medicine, Rochester, Michigan, United States
  • Nader Sheibani
    Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States
  • Mong Wang
    Physiology, Augusta University, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   Mohamed Al-Shabrawey U.S. Patent Application No.: 16/106,421, Code P (Patent); Amany Tawfik None; Nader Sheibani None; Mong Wang U.S. Patent Application No.: 16/106,421, Code P (Patent)
  • Footnotes
    Support  AHA Grant-in-Aid AHASE00144 and R01 R01 EY030054-01A1
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2161 – F0224. doi:
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      Mohamed Al-Sayed Al-Shabrawey, Amany M Tawfik, Nader Sheibani, Mong Wang; EET Blockade: A New Method to Optimize AT1 Blockade in the Treatment of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2161 – F0224.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The activation of the renin-angiotensin system (RAS) contributes to the destruction of blood-retinal barrier (BRB) and neovascularization in diabetic retinopathy (DR). Although blocking RAS in clinical studies reduced the incidence of DR, it did not reduce the progression of DR. The goal of this study was to decipher the role of epoxyeicosatrienoic acids (EETs), cytochrome P450 (CYP)-derived eicosanoids, and EETs degrading enzyme soluble epoxide hydrolase (sEH) in angiotensin II (Ang II)- and diabetes-induced retinal microvascular damage. We also determine the interactions between EETs/sEH and angiotensin receptor-1 (AT1) in the retina.

Methods : We induced experimental diabetes in wild-type and sEH knockout mice by intraperitoneal injection of streptozotocin (STZ). Some mice received chronic treatment with Ang II via SC minipump (3 mg/kg/day), with or without AT1 blocker telmisartan (2.5 mg/kg/day). Some mice received intravitreal injection of Ang II with or without 11,12 EET. Integrity of blood retinal barrier (BRB) was assessed by analysis of albumin leakage in the retina. Analysis of the plasma levels of bioactive lipids in normal and diabetic mice was done using LC/MS/MS.

Results : Ang II increases retinal expression of sEH by 2.8-fold (2.84 ± 1.1 vs. 1 ± 0.08, P < 0.05, n = 4), which is blunted by AT1 blockade. Moreover, sEH blockade and knockout (KO), which accumulate EETs, enhance Ang II-induced BRB injury as shown by 1.58 folds increase in retinal albumin leakage (1.58 ± 0.4 vs. 1 ± 0.13, P < 0.05, n = 4) and 2.8-folds (2.8 ± 1.7 vs. 1 ± 0.09, P < 0.05, n = 4), respectively. These results were confirmed by fluorescein angiogram (FA) analysis. Administration of synthetic 11,12-EET enhances intravitreal Ang II-induced retinal albumin leakage by 2.2-fold (2.2 ± 0.5 vs. 1 ± 0.18, P < 0.05, n = 4). In addition, 11,12-EET induces retinal hyperpermeability by FA and retinal albumin leakage. Moreover, sEH KO potentiates diabetes-induced retinal damage. This was associated with upregulation of retinal vascular endothelial growth factor (VEGF) and glucose transporter-1 (GLUT-1).

Conclusions : Our data indicate that in DR, the activation of retinal AT1 triggers a compensation mechanism by increasing retinal sEH, thereby reducing the production of EETs. Therefore, the combined use of EETs blockers and AT1 blockers is expected to become a new treatment strategy to prevent or reduce DR.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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