ACE2 on gut barrier dysfunction and BRB disruption

这个项目的首要目标是确定血管紧张素转换酶2的作用。 (ACE2)在糖尿病肠道中，它如何影响高血糖和血糖变异性，从而促进 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ACE2组成，它将血管紧张素II(Ang-II)转化为血管紧张素1-7(Ang-1-7)。Ang-1-7反对 Ang-II通过对MAS受体的作用发挥作用。而全身(内分泌)RAS 与局部(组织)RAS一起工作，如眼睛和肠道中的RAS，以实现健康的动态平衡 糖尿病保护性RAS的关键成分丢失可导致广泛的病理改变。文学作品 我们的初步数据支持糖尿病会导致ACE2在肠道、骨骼中的表达缺失 骨髓和视网膜。血糖变异性与DR的发病机制有关。肠道血管紧张素转换酶2可调节 通过调节色氨酸吸收和胰岛素释放，以及通过产生血管紧张素-1- 7来自血管紧张素Ⅱ。血管紧张素1-7通过与mas受体结合而阻断葡萄糖在肠道中的转运，类似于 在胰腺中描述的东西。在此基础上，我们假设：在T2D中，肠细胞的丢失 ACE2减少：i)色氨酸 摄取与胰岛素分泌 导致高血糖；ii)MAS 受体激活增加肠道葡萄糖吸收；以及iii)肠道屏障完整性导致 肠道微生物多肽泄漏进入血液循环。所有这三种机制都会增加视网膜 通透性和激活免疫细胞促进DR病理。目标1将测试是否存在调节失调 肠上皮细胞中的ACE2导致1)B0AT1减少INTIN导致色氨酸转运中断 分泌和ii)减少MAS受体激活，导致肠道葡萄糖吸收增加。 Aim 2将在db/db小鼠身上测试肠道血管紧张素转换酶2的丢失是否会导致肠道循环水平的增加。 将激活视网膜内皮细胞上的TLRs并导致视网膜增加的微生物多肽 白血球淤滞和血视网膜屏障功能障碍。目标3将检查营养食品或益生菌是否可以 恢复db/db小鼠肠道RAS(ACE2/Ang-1-7/MAS)的平衡以防止发生 Impact博士：我们提出了一种新的血糖稳态恶化和升高的机制 糖尿病中的血糖变异性-ACE2：B0AT1寡聚体形式的ACE2的功能丧失(独有 肠上皮细胞)和肠道Ang 1-7水平降低导致肠道MAS受体减少 激活。肠道RAS的失调会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.