Role of Endothelial ADAM17 in Early Vascular Changes Associated with Diabetic Retinopathy
Lamiaa Shalaby1, Menaka Thounaojam1, Amany Tawfik2
1Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Abstract:
ADAM17, a disintegrin and metalloproteinase 17, is a transmembrane metalloproteinase that regulates bioavailability of multiple membrane-bound proteins via ectodomain shedding. ADAM17 activity was shown to contribute to a number of vascular pathologies, but its role in the context of diabetic retinopathy (DR) is not determined. We found that expression and enzymatic activity of ADAM17 are upregulated in human diabetic postmortem retinas and a mouse model of streptozotocin-induced diabetes. To further investigate the contribution of ADAM17 to vascular alterations associated with DR, we used human retinal endothelial cells (HREC) treated with ADAM17 neutralizing antibodies and exposed to glucidic stress and streptozotocin-induced endothelial ADAM17 knockout mice. Evaluation of vascular permeability, vascular inflammation, and oxidative stress was performed. Loss of ADAM17 in endothelial cells markedly reduced oxidative stress evidenced by decreased levels of superoxide, 3-nitrotyrosine, and 4-hydroxynonenal and decreased leukocyte-endothelium adhesive interactions in vivo and in vitro. Reduced leukostasis was associated with decreased vascular permeability and was accompanied by downregulation of intercellular adhesion molecule-1 expression. Reduction in oxidative stress in HREC was associated with downregulation of NAD(P)H oxidase 4 (Nox4) expression. Our data suggest a role for endothelial ADAM17 in DR pathogenesis and identify ADAM17 as a potential new therapeutic target for DR.
Insights
Endothelial ADAM17 (a disintegrin and metalloproteinase 17) is upregulated in diabetic retinopathy (DR). Reducing ADAM17 lessens oxidative stress, inflammation, and vascular permeability, suggesting it as a therapeutic target for DR.
Area of Science:
- Vascular Biology
- Ophthalmology
- Biochemistry
Background:
- ADAM17 (a disintegrin and metalloproteinase 17) is a metalloproteinase involved in vascular pathologies.
- Its specific role in diabetic retinopathy (DR) remains undetermined.
- Expression and activity of ADAM17 are elevated in diabetic retinas.
Purpose of the Study:
- To investigate the role of endothelial ADAM17 in diabetic retinopathy pathogenesis.
- To determine if targeting ADAM17 can ameliorate DR-associated vascular alterations.
Main Methods:
- Studied human diabetic retinas and a mouse model of diabetes.
- Utilized human retinal endothelial cells (HREC) under glucidic stress.
- Employed endothelial ADAM17 knockout mice and ADAM17 neutralizing antibodies.
Main Results:
- Loss of ADAM17 reduced oxidative stress markers (superoxide, 3-nitrotyrosine, 4-hydroxynonenal) and leukostasis.
- Reduced leukostasis correlated with decreased vascular permeability and ICAM-1 expression.
- In HREC, ADAM17 reduction led to decreased NAD(P)H oxidase 4 (Nox4) expression.
Conclusions:
- Endothelial ADAM17 plays a significant role in diabetic retinopathy pathogenesis.
- ADAM17 inhibition effectively reduces oxidative stress, inflammation, and vascular leakage.
- ADAM17 presents a promising therapeutic target for managing diabetic retinopathy.
