Departments of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Department of Medicine and Institute of Medical Science, University of Toronto, Toronto, Canada.
Sci Rep. 2020 Mar 6;10(1):4225. doi: 10.1038/s41598-020-61250-5.
Angiotensin-[1-7] (Ang-[1-7]) antagonize the actions of the renin-angiotensin-system via the Mas receptor and thereby exert renoprotective effects. Murine recombinant angiotensin-converting enzyme (ACE)2 was reported to show renoprotective effects in an experimental Alport syndrome model; however, the protective effect of direct administration of Ang-[1-7] is unknown. Here, we used Col4a3 mice as a model of Alport syndrome, which were treated with saline or Ang- [1-7]; saline-treated wild-type mice were used as a control group. The mice were continuously infused with saline or Ang-[1-7] (25 μg/kg/h) using osmotic mini-pumps. Col4a3 mice showed increased α-smooth muscle actin (SMA), collagen, and fibronectin expression levels, which were attenuated by Ang-[1-7] treatment. Moreover, Ang-[1-7] alleviated activation of transforming growth factor-β/Smad signaling, and attenuated the protein expression of ED-1 and heme oxygenase-1, indicating reduction of renal inflammation. Ang-[1-7] treatment further reduced the expression levels of inflammatory cytokines and adhesion molecules and attenuated apoptosis in human kidney cells. Finally, Ang-[1-7] downregulated TNF-α converting enzyme and upregulated ACE2 expression. Thus, treatment with Ang-[1-7] altered the ACE2-Ang-[1-7]-Mas receptor axis in the kidneys of Col4a3 mice to attenuate the nephropathy progression of Alport syndrome.
血管紧张素-[1-7]（Ang-[1-7]）通过 Mas 受体拮抗肾素-血管紧张素系统的作用，从而发挥肾脏保护作用。有报道称，鼠重组血管紧张素转换酶（ACE）2 在实验性 Alport 综合征模型中显示出肾脏保护作用；然而，直接给予 Ang-[1-7]的保护作用尚不清楚。在这里，我们使用 Col4a3 小鼠作为 Alport 综合征的模型，用盐水或 Ang-[1-7]处理；用盐水处理的野生型小鼠作为对照组。使用渗透微型泵持续向小鼠输注盐水或 Ang-[1-7]（25μg/kg/h）。Col4a3 小鼠α-平滑肌肌动蛋白（SMA）、胶原和纤维连接蛋白的表达水平增加，而 Ang-[1-7]处理则减弱了这种增加。此外，Ang-[1-7]减轻了转化生长因子-β/Smad 信号的激活，并减轻了 ED-1 和血红素加氧酶-1 的蛋白表达，表明肾脏炎症减轻。Ang-[1-7]处理进一步降低了人肾细胞中炎症细胞因子和黏附分子的表达水平，并减弱了细胞凋亡。最后，Ang-[1-7]下调 TNF-α 转化酶并上调 ACE2 表达。因此，Ang-[1-7]治疗改变了 Col4a3 小鼠肾脏中的 ACE2-Ang-[1-7]-Mas 受体轴，从而减轻 Alport 综合征的肾脏病变进展。
