ACE2 on gut barrier dysfunction and BRB disruption

本项目的首要目标是确定血管紧张素转换酶2在 （ACE 2）在糖尿病肠道，它如何影响高血糖和血糖变异性，从而有助于 糖尿病视网膜病变（DR）的发病机制。肾素血管紧张素系统（RAS）的保护臂 由ACE 2组成，ACE 2将血管紧张素II（Ang-II）转化为血管紧张素1 - 7（Ang-1 - 7）。Ang-1 - 7反对 Ang-II通过其对MAS受体的作用而产生的作用。而全身（内分泌）RAS 与局部（组织）RAS（如眼睛和肠道中的RAS）一起工作，以实现健康的体内平衡， 糖尿病保护性RAS的关键组分的丧失可导致广泛的病理学。文献 我们的初步数据支持糖尿病导致肠、骨和胃中ACE2表达的缺失， 骨髓和视网膜。糖尿病视网膜病变的发病机制与糖基化的变异有关。肠ACE2可以调节 通过调节色氨酸的吸收和肠促胰岛素的释放以及通过产生血管紧张素1- 7来自Luminal Ang II。血管紧张素1 - 7通过与Mas受体结合，可阻断葡萄糖在肠道中的转运， 在胰腺中所描述的。基于此，我们假设：在T2D中，肠上皮细胞的损失 ACE2降低：i）色氨酸 摄取和肠促胰岛素分泌 导致高血糖症; ii）MAS 受体活化增加肠葡萄糖吸收;和iii）肠屏障完整性， 肠道微生物肽渗漏到循环中。所有这三种机制都会增加视网膜 渗透性和活化免疫细胞促进DR病理。目标1将测试是否失调 肠上皮中的ACE2导致i）通过B0AT 1中断色氨酸转运，降低肠促胰岛素 ii）降低MAS受体活化，导致肠中葡萄糖吸收增加。 目的2将测试在db/db小鼠中，肠ACE2的损失是否会导致肠循环水平的增加。 微生物肽，将激活视网膜内皮细胞上的TLR，并导致视网膜内皮细胞增殖增加。 白细胞停滞和血视网膜屏障功能障碍。目标3将检查营养品或益生菌是否可以 恢复db/db小鼠肠道RAS（ACE2/Ang-1 - 7/MAS）的平衡，以防止 博士影响：我们提出了一种新的机制，使葡萄糖稳态恶化， 糖尿病中的葡萄糖变异性-ACE2的ACE2：B0AT 1寡聚体形式的功能丧失（独特于 肠上皮细胞）和降低的肠Ang 1 - 7水平导致更少的肠MAS受体 activation.肠道RAS失调可导致严重的视网膜病变，促进DR。

The overarching goal of this project is to determine the role of angiotensin converting enzyme 2 (ACE2) in the diabetic gut, how it impacts hyperglycemia and glycemic variability, and thus contributes to the pathogenesis of diabetic retinopathy (DR). The protective arm of the renin angiotensin system (RAS) consists of ACE2, which converts angiotensin II (Ang-II) to angiotensin 1-7 (Ang-1-7). Ang-1-7 opposes the effects of Ang-II by virtue of its actions on the MAS receptor. While the systemic (endocrine) RAS works with local (tissue) RAS such as that in the eye and gut to achieve homeostasis in health, in diabetes loss of key components of the protective RAS can lead to widespread pathology. The literature and our preliminary data support that diabetes results in loss of expression of ACE2 in the gut, bone marrow, and retina. Glycemic variability is implicated in DR pathogenesis. Intestinal ACE2 can regulate glucose homeostasis by modulating tryptophan absorption and incretin release and by generating Ang 1- 7 from luminal Ang II. Ang 1-7 by binding to Mas receptor can block glucose transport in the gut similar to what has been described in the pancreas. Based on this, we hypothesis: In T2D, loss of enterocyte ACE2 decreases: i) tryptophan uptake and incretin secretion leading to hyperglycemia; ii) MAS receptor activation increasing gut glucose absorption; and iii) gut barrier integrity resulting in leakage of gut microbial peptides into the circulation. All three mechanisms increase retinal permeability and activating immune cells promoting DR pathology. Aim 1 will test if dysregulation of ACE2 in the gut epithelium results in i) interruption of tryptophan transport by B0AT1 decreasing incretin secretion and ii) reduced MAS receptor activation leading to increased glucose absorption in the gut. Aim 2 will test if in db/db mice, loss of intestinal ACE2 will result in increasing circulating levels of gut microbial peptides that will activate TLRs on retinal endothelial cells and lead to increased retinal leukostasis and blood retinal barrier dysfunction. Aim 3 will examine if nutraceuticals or probiotics can restore the balance of the intestinal RAS (ACE2/Ang-1-7/MAS) in db/db mice to prevent development of DR. Impact: We propose a novel mechanism for deterioration of glucose homeostasis and increased glucose variability in diabetes- the loss of function of the ACE2:B0AT1 oligomer form of ACE2 (unique to the intestinal epithelium) and reduced levels of intestinal Ang 1-7 resulting in less intestinal MAS receptor activation. The dysregulated intestinal RAS can lead to serious retinal pathology promoting DR.