Deletion of angiotensin-converting enzyme 2 exacerbates renal inflammation and injury in apolipoprotein E-deficient mice through modulation of the nephrin and TNF-alpha-TNFRSF1A signaling.
Deletion of angiotensin-converting enzyme 2 exacerbates renal inflammation and injury in apolipoprotein E-deficient mice through modulation of the nephrin and TNF-alpha-TNFRSF1A signaling.
复制标题
血管紧张素转换酶 2 的缺失会通过调节去氧肾上腺素和 TNF-α-TNFRSF1A 信号传导，加剧载脂蛋白 E 缺陷小鼠的肾脏炎症和损伤。
DOI：
10.1186/s12967-015-0616-8
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发表时间：
2015-08-06
影响因子：
7.4
通讯作者：
Zhong JC
中科院分区：
文献类型：
--
作者：
Jin HY;Chen LJ;Zhang ZZ;Xu YL;Song B;Xu R;Oudit GY;Gao PJ;Zhu DL;Zhong JC
背景肾素-血管紧张素系统（RAS）与动脉粥样硬化病变和慢性肾脏疾病的进展有关。我们检查了血管紧张素转换酶 2 (ACE2) 在载脂蛋白 E (ApoE) 敲除 (KO) 肾脏中的调节作用。方法使用 C57BL/6 背景下 3 个月大的野生型、ApoEKO、ACE2KO 和 ApoE/ACE2 双 KO (DKO) 小鼠。 ApoEKO 小鼠被随机每天给予 Ang II (1.5 mg/kg) 和/或人重组 ACE2 (rhACE2；2 mg/kg)，持续 2 周。我们检查了小鼠肾脏中促炎细胞因子、肾脏超微结构和病理信号传导的变化。结果在 ApoEKO 肾脏中观察到 ACE2 和去氧肾上腺素水平下调。遗传性 ACE2 缺失导致 ApoE/ACE2 DKO 小鼠肾脏中收缩压水平和 Ang II 1 型受体表达适度升高，并减少去氧肾上腺素表达，同时肾脏 Ang-(1-7) 水平降低。这些变化与肾脏超氧化物生成、NADPH 氧化酶 (NOX) 4 和促炎因子水平的显着增加有关，包括白细胞介素 (IL)-1β、IL-6、IL-17A、RANTES、ICAM-1、肿瘤坏死因子-α (TNF-α) 和 TNFRSF1A。 ApoE/ACE2 DKO 小鼠和注入 Ang II 的 ApoEKO 小鼠的肾功能障碍和超微结构损伤加重，血浆肌酐、血尿素氮水平升高，血浆和肾脏中 Ang II 水平升高。补充 rhACE2 可显着挽救 ApoEKO 小鼠中 Ang II 介导的肾 ACE2 和去氧肾上腺素水平降低，同时肾 Ang-(1-7) 水平增加。更重要的是，rhACE2 治疗通过抑制 NOX4 和 TNF-α-TNFRSF1A 信号传导，显着逆转 ApoEKO 小鼠中 Ang II 诱导的肾脏炎症、超氧化物生成、肾功能障碍和不良肾损伤。然而，rhACE2 对肾脏 NOX2 和 TNFRSF1B 表达以及循环脂质水平没有影响。结论ACE2 缺乏通过调节去氧肾上腺素、NOX4 和 TNF-α-TNFRSF1A 信号传导，加剧了 ApoE 突变小鼠的肾脏炎症、氧化应激和不良肾损伤。补充 rhACE2 可以减轻 ApoE 突变小鼠的炎症、肾功能障碍和肾小球损伤，这些损伤与 Ang-(1-7) 水平和去氧肾上腺素表达上调以及 TNF-α-TNFRSF1A 信号传导抑制相关。旨在增强 ACE2/Ang-(1-7) 作用的策略可能对动脉粥样硬化性肾损伤和肾脏疾病具有重要的治疗潜力。
BackgroundThe renin-angiotensin system (RAS) has been implicated in atherosclerotic lesions and progression to chronic kidney diseases. We examined regulatory roles of angiotensin-converting enzyme 2 (ACE2) in the apolipoprotein E (ApoE) knockout (KO) kidneys.MethodsThe 3-month-old wild-type, ApoEKO, ACE2KO and ApoE/ACE2 double-KO (DKO) mice in a C57BL/6 background were used. The ApoEKO mice were randomized to daily deliver either Ang II (1.5 mg/kg) and/or human recombinant ACE2 (rhACE2; 2 mg/kg) for 2 weeks. We examined changes in pro-inflammatory cytokines, renal ultrastructure, and pathological signaling in mouse kidneys.ResultsDownregulation of ACE2 and nephrin levels was observed in ApoEKO kidneys. Genetic ACE2 deletion resulted in modest elevations in systolic blood pressure levels and Ang II type 1 receptor expression and reduced nephrin expression in kidneys of the ApoE/ACE2 DKO mice with a decrease in renal Ang-(1-7) levels. These changes were linked with marked increases in renal superoxide generation, NADPH oxidase (NOX) 4 and proinflammatory factors levels, including interleukin (IL)-1beta, IL-6, IL-17A, RANTES, ICAM-1, Tumor necrosis factor-alpha (TNF-alpha) and TNFRSF1A. Renal dysfunction and ultrastructure injury were aggravated in the ApoE/ACE2 DKO mice and Ang II-infused ApoEKO mice with increased plasma levels of creatinine, blood urea nitrogen and enhanced levels of Ang II in plasma and kidneys. The Ang II-mediated reductions of renal ACE2 and nephrin levels in ApoEKO mice were remarkably rescued by rhACE2 supplementation, along with augmentation of renal Ang-(1-7) levels. More importantly, rhACE2 treatment significantly reversed Ang II-induced renal inflammation, superoxide generation, kidney dysfunction and adverse renal injury in ApoEKO mice with suppression of the NOX4 and TNF-alpha-TNFRSF1A signaling. However, rhACE2 had no effect on renal NOX2 and TNFRSF1B expression and circulating lipid levels.ConclusionsACE2 deficiency exacerbates kidney inflammation, oxidative stress and adverse renal injury in the ApoE-mutant mice through modulation of the nephrin, NOX4 and TNF-alpha-TNFRSF1A signaling. While rhACE2 supplementation alleviates inflammation, renal dysfunction and glomerulus injury in the ApoE-mutant mice associated with upregulations of Ang-(1-7) levels and nephrin expression and suppression of the TNF-alpha-TNFRSF1A signaling. Strategies aimed at enhancing the ACE2/Ang-(1-7) actions may have important therapeutic potential for atherosclerotic renal injury and kidney diseases.