Shalaby Lamiaa, Thounaojam Menaka, Tawfik Amany, Li Junnan, Hussein Khaled, Jahng Wan Jin, Al-Shabrawey Mohamed, Kwok Hang Fai, Bartoli Manuela, Gutsaeva Diana
Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA.
J Clin Med. 2020 Feb 2;9(2):400. doi: 10.3390/jcm9020400.
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 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.
解整合素金属蛋白酶17（ADAM17）是一种跨膜金属蛋白酶，可通过胞外域脱落调节多种膜结合蛋白的生物利用度。ADAM17的活性已被证明与多种血管病变有关，但其在糖尿病视网膜病变（DR）中的作用尚未确定。我们发现，ADAM17的表达和酶活性在人类糖尿病视网膜以及链脲佐菌素诱导的糖尿病小鼠模型中上调。为了进一步研究ADAM17对与DR相关的血管改变的作用，我们使用了用ADAM17中和抗体处理并暴露于糖应激的人视网膜内皮细胞（HREC）以及链脲佐菌素诱导的内皮ADAM17基因敲除小鼠。对血管通透性、血管炎症和氧化应激进行了评估。内皮细胞中ADAM17的缺失显著降低了氧化应激，表现为超氧化物、3-硝基酪氨酸和4-羟基壬烯醛水平降低，以及体内外白细胞与内皮细胞黏附相互作用减少。白细胞淤滞减少与血管通透性降低相关，并伴有细胞间黏附分子-1表达下调。HREC中氧化应激的降低与NAD(P)H氧化酶4（Nox4）表达下调相关。我们的数据表明内皮ADAM17在DR发病机制中起作用，并将ADAM17确定为DR潜在的新治疗靶点。
