Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
Hypertension. 2011 Feb;57(2):314-22. doi: 10.1161/HYPERTENSIONAHA.110.164244. Epub 2010 Dec 28.
Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase capable of metabolizing angiotensin (Ang) II into Ang 1 to 7. We hypothesized that ACE2 is a negative regulator of Ang II signaling and its adverse effects on the kidneys. Ang II infusion (1.5 mg/kg⁻¹/d⁻¹) for 4 days resulted in higher renal Ang II levels and increased nicotinamide adenine dinucleotide phosphate oxidase activity in ACE2 knockout (Ace2(-/y)) mice compared to wild-type mice. Expression of proinflammatory cytokines, interleukin-1β and chemokine (C-C motif) ligand 5, were increased in association with greater activation of extracellular-regulated kinase 1/2 and increase of protein kinase C-α levels. These changes were associated with increased expression of fibrosis-associated genes (α-smooth muscle actin, transforming growth factor-β, procollagen type Iα1) and increased protein levels of collagen I with histological evidence of increased tubulointerstitial fibrosis. Ang II-infused wild-type mice were then treated with recombinant human ACE2 (2 mg/kg⁻¹/d⁻¹, intraperitoneal). Daily treatment with recombinant human ACE2 reduced Ang II-induced pressor response and normalized renal Ang II levels and oxidative stress. These changes were associated with a suppression of Ang II-mediated activation of extracellular-regulated kinase 1/2 and protein kinase C pathway and Ang II-mediated renal fibrosis and T-lymphocyte-mediated inflammation. We conclude that loss of ACE2 enhances renal Ang II levels and Ang II-induced renal oxidative stress, resulting in greater renal injury, whereas recombinant human ACE2 prevents Ang II-induced hypertension, renal oxidative stress, and tubulointerstitial fibrosis. ACE2 is an important negative regulator of Ang II-induced renal disease and enhancing ACE2 action may have therapeutic potential for patients with kidney disease.
血管紧张素转换酶 2（ACE2）是一种单羧肽酶，能够将血管紧张素（Ang）II 代谢为 Ang 1 至 7。我们假设 ACE2 是 Ang II 信号的负调节剂及其对肾脏的不良影响。与野生型小鼠相比，Ang II 输注（1.5 mg/kg⁻¹/d⁻¹）4 天导致 ACE2 敲除（Ace2(-/y)）小鼠的肾脏 Ang II 水平升高和烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性增加。促炎细胞因子白细胞介素-1β和趋化因子（C-C 基序）配体 5 的表达增加，与细胞外调节激酶 1/2 的更激活和蛋白激酶 C-α水平的增加有关。这些变化与纤维化相关基因（α-平滑肌肌动蛋白、转化生长因子-β、I 型前胶原α1）的表达增加以及胶原蛋白 I 的蛋白水平增加有关，组织学证据表明肾小管间质纤维化增加。然后，用重组人 ACE2（2 mg/kg⁻¹/d⁻¹，腹腔内）治疗 Ang II 输注的野生型小鼠。每天用重组人 ACE2 治疗可降低 Ang II 引起的升压反应并使肾脏 Ang II 水平和氧化应激正常化。这些变化与 Ang II 介导的细胞外调节激酶 1/2 和蛋白激酶 C 途径的激活以及 Ang II 介导的肾脏纤维化和 T 淋巴细胞介导的炎症的抑制有关。我们得出结论，ACE2 的缺失增强了肾脏 Ang II 水平和 Ang II 诱导的肾脏氧化应激，导致更大的肾脏损伤，而重组人 ACE2 可预防 Ang II 诱导的高血压、肾脏氧化应激和肾小管间质纤维化。ACE2 是 Ang II 诱导的肾脏疾病的重要负调节剂，增强 ACE2 作用可能对肾脏疾病患者具有治疗潜力。
