Clinical studies have suggested that the renin-angiotensin system (RAS) may be a promising therapeutic target in treating diabetic retinopathy (DR). While AT1 receptor blockade decreased the incidence of DR in the DIRECT trial, it did not reduce the DR progression. Lack of understanding of the molecular mechanism of retinal microvascular damage induced by RAS is a critical barrier to the use of RAS blockade in preventing or treating DR. The purpose of this study is to investigate the interaction between soluble epoxide hydrolase (sEH) and the AT1 receptor in Angiotensin II (Ang II)- and diabetes-induced retinal microvascular damage. We demonstrate that Ang II increases retinal sEH levels, which is blunted by an AT1 blocker; administration of 11,12-epoxyeicosatrienoic acid (EET) exacerbates intravitreal Ang II-induced retinal albumin leakage; while sEH knockout (KO) and blockade reduce Ang II-induced retinal vascular remodeling, sEH KO causes retinal vascular leakage in Ang II-sEH KO mice; and sEH KO potentiates diabetes-induced retinal damage via promoting retinal vascular endothelial growth factor (VEGF) but reducing expression of tight junction proteins (ZO-1 and occludin). Our studies hold the promise of providing a new strategy, the use of combined EETs blockade with AT1 blocker, to prevent or reduce DR.

中文翻译：

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可溶性环氧化物水解酶与 AT1 受体在视网膜微血管损伤中的新型相互作用。


临床研究表明，肾素-血管紧张素系统（RAS）可能是治疗糖尿病视网膜病变（DR）的一个有前景的治疗靶点。虽然在 DIRECT 试验中 AT1 受体阻断降低了 DR 的发生率，但它并没有减少 DR 的进展。对 RAS 引起的视网膜微血管损伤的分子机制缺乏了解是使用 RAS 阻断来预防或治疗 DR 的关键障碍。本研究的目的是研究血管紧张素 II (Ang II) 和糖尿病引起的视网膜微血管损伤中可溶性环氧化物水解酶 (sEH) 和 AT1 受体之间的相互作用。我们证明 Ang II 会增加视网膜 sEH 水平，而 AT1 阻滞剂会减弱这种水平；给予 11,12-环氧二十碳三烯酸 (EET) 会加剧玻璃体内血管紧张素 II 诱导的视网膜白蛋白渗漏； sEH 敲除 (KO) 和阻断可减少 Ang II 诱导的视网膜血管重塑，而 sEH KO 会导致 Ang II-sEH KO 小鼠视网膜血管渗漏； sEH KO 通过促进视网膜血管内皮生长因子 (VEGF) 但减少紧密连接蛋白（ZO-1 和 occludin）的表达来增强糖尿病引起的视网膜损伤。我们的研究有望提供一种新策略，即联合使用 EET 阻断剂和 AT1 阻断剂来预防或减少 DR。