Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia, Universidad Catolica de Chile, Santiago 8330024, Chile; Division Enfermedades Cardiovasculares, Escuela de Medicina, Facultad de Medicina, Pontificia Universidad Catolica de Chile, Santiago 8330024, Chile.
Departmento de Ciencias Basicas Biomedicas, Facultad de Ciencias de la Salud, Universidad de Talca, Chile.
Biochem Pharmacol. 2018 Oct;156:357-370. doi: 10.1016/j.bcp.2018.08.045. Epub 2018 Sep 1.
Hypertension-induced cardiovascular and renal damage can be mediated by activation of the renin-angiotensin-aldosterone system. There are different factors beyond renin-angiotensin-aldosterone system involved in hypertension and renal damage. Inflammation has emerged as an important mediator of hypertension and cardiovascular and kidney damage. Angiotensin-(1-9), a peptide of the renin-angiotensin system, counter-regulates both the physiological and pathological actions of angiotensin II. Recent data has shown that angiotensin-(1-9) protects the heart and blood vessels from adverse cardiovascular remodeling in experimental models of hypertension and/or heart failure and reduces cardiac fibrosis in stroke-prone, spontaneously hypertensive rats. These effects are mediated by the angiotensin II type 2 receptor (AT2R). However, it remains unknown whether angiotensin-(1-9) also has an anti-inflammatory effect. In the present study, we investigate whether angiotensin-(1-9) reduces inflammation and fibrosis in the heart, arteries, and kidney in a DOCA-salt hypertensive model and explore the mechanisms underlying the amelioration of end-organ damage. DOCA-salt hypertensive rats received: a) vehicle, b) angiotensin-(1-9), c) PD123319 (AT2R blocker), d) angiotensin-(1-9) plus A779 (a Mas receptor blocker) or e) angiotensin-(1-9) plus PD123319, and sham rats were used as a control. Our results showed that angiotensin-(1-9) decreased hypertension and increased vasodilation in DOCA-salt hypertensive rats. These actions were partially inhibited by PD123319. Moreover, angiotensin-(1-9) decreased diuresis, fibrosis, and inflammation. These beneficial effects were not mediated by Mas or AT2R blockers. We concluded that angiotensin-(1-9) protects against volume overload-induced hypertensive cardiovascular and kidney damage by decreasing inflammation in the heart, aortic wall, and kidney, through mechanisms independent of the Mas or AT2R.
高血压引起的心血管和肾脏损害可通过肾素-血管紧张素-醛固酮系统的激活来介导。除了肾素-血管紧张素-醛固酮系统之外，还有许多其他因素与高血压和肾脏损害有关。炎症已成为高血压、心血管和肾脏损害的一个重要介质。血管紧张素-(1-9)是肾素-血管紧张素系统的一种肽，它对血管紧张素 II 的生理和病理作用具有反向调节作用。最近的数据表明，血管紧张素-(1-9)可保护心脏和血管免受高血压和/或心力衰竭实验模型中的不良心血管重构，并减少易中风的自发性高血压大鼠的心脏纤维化。这些作用是通过血管紧张素 II 型 2 型受体 (AT2R) 介导的。然而，目前尚不清楚血管紧张素-(1-9)是否也具有抗炎作用。在本研究中，我们研究了血管紧张素-(1-9)是否可降低 DOCA-盐高血压模型中心脏、动脉和肾脏的炎症和纤维化，并探讨了改善终末器官损伤的机制。DOCA-盐高血压大鼠接受以下处理：a) 载体，b) 血管紧张素-(1-9)，c) PD123319（AT2R 阻滞剂），d) 血管紧张素-(1-9)加 A779（Mas 受体阻滞剂）或 e) 血管紧张素-(1-9)加 PD123319，假手术大鼠作为对照。我们的结果表明，血管紧张素-(1-9)降低了 DOCA-盐高血压大鼠的高血压并增加了血管舒张。这些作用部分被 PD123319 抑制。此外，血管紧张素-(1-9)降低了利尿、纤维化和炎症。这些有益作用不是由 Mas 或 AT2R 阻滞剂介导的。我们得出结论，血管紧张素-(1-9)通过降低心脏、主动脉壁和肾脏的炎症，减轻容量超负荷引起的高血压心血管和肾脏损害，其作用机制独立于 Mas 或 AT2R。
