Chen Lai-Jiang, Xu Ying-Le, Song Bei, Yu Hui-Min, Oudit Gavin Y, Xu Ran, Zhang Zhen-Zhou, Jin Hai-Yan, Chang Qing, Zhu Ding-Liang, Zhong Jiu-Chang
State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China; Institute of Health Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China.
State Key Laboratory of Medical Genomics, Pôle Sino-Français de Recherches en Science du Vivant et Génomique, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai 200025, China.
Peptides. 2016 May;79:49-57. doi: 10.1016/j.peptides.2016.03.008. Epub 2016 Mar 24.
Angiotensin-converting enzyme 2 (ACE2) has been shown to prevent atherosclerotic lesions and renal inflammation. However, little was elucidated upon the effects and mechanisms of ACE2 in atherosclerotic kidney fibrosis progression. Here, we examined regulatory roles of ACE2 in renal fibrosis in the apolipoprotein E (ApoE) knockout (KO) mice. The ApoEKO mice were randomized to daily deliver either angiotensin (Ang) II (1.5mg/kg) and/or human recombinant ACE2 (rhACE2; 2mg/kg) for 2 weeks. Downregulation of ACE2 and upregulation of phosphorylated Akt, mTOR and ERK1/2 levels were observed in ApoEKO kidneys. Ang II infusion led to increased tubulointerstitial fibrosis in the ApoEKO mice with greater activation of the mTOR/ERK1/2 signaling. The Ang II-mediated renal fibrosis and structural injury were strikingly rescued by rhACE2 supplementation, associated with reduced mRNA expression of TGF-β1 and collagen I and elevated renal Ang-(1-7) levels. In cultured mouse kidney fibroblasts, exposure with Ang II (100nmolL(-1)) resulted in obvious elevations in superoxide generation, phosphorylated levels of mTOR and ERK1/2 as well as mRNA levels of TGF-β1, collagen I and fibronectin 1, which were dramatically prevented by rhACE2 (1mgmL(-1)) or mTOR inhibitor rapamycin (10μmolL(-1)). These protective effects of rhACE2 were eradicated by the Ang-(1-7)/Mas receptor antagonist A779 (1μmolL(-1)). Our results demonstrate the importance of ACE2 in amelioration of kidney fibrosis and renal injury in the ApoE-mutant mice via modulation of the mTOR/ERK signaling and renal Ang-(1-7)/Ang II balance, thus indicating potential therapeutic strategies by enhancing ACE2 action for preventing atherosclerosis and fibrosis-associated kidney disorders.
血管紧张素转换酶2（ACE2）已被证明可预防动脉粥样硬化病变和肾脏炎症。然而，关于ACE2在动脉粥样硬化性肾纤维化进展中的作用和机制，人们了解甚少。在此，我们研究了ACE2在载脂蛋白E（ApoE）基因敲除（KO）小鼠肾纤维化中的调节作用。将ApoE KO小鼠随机分组，每天给予血管紧张素（Ang）II（1.5mg/kg）和/或人重组ACE2（rhACE2；2mg/kg），持续2周。在ApoE KO小鼠的肾脏中观察到ACE2下调以及磷酸化Akt、mTOR和ERK1/2水平上调。输注Ang II导致ApoE KO小鼠肾小管间质纤维化增加，mTOR/ERK1/2信号的激活更强。补充rhACE2可显著挽救Ang II介导的肾纤维化和结构损伤，这与TGF-β1和胶原蛋白I的mRNA表达降低以及肾脏Ang-(1-7)水平升高有关。在培养的小鼠肾成纤维细胞中，用Ang II（100nmolL(-1)）处理导致超氧化物生成、mTOR和ERK1/2的磷酸化水平以及TGF-β1、胶原蛋白I和纤连蛋白1的mRNA水平明显升高，而rhACE2（1mgmL(-1)）或mTOR抑制剂雷帕霉素（10μmolL(-1)）可显著抑制这些变化。Ang-(1-7)/Mas受体拮抗剂A779（1μmolL(-1)）消除了rhACE2的这些保护作用。我们的结果表明，ACE2通过调节mTOR/ERK信号和肾脏Ang-(1-7)/Ang II平衡，在改善ApoE突变小鼠的肾纤维化和肾损伤方面具有重要作用，从而提示通过增强ACE2作用来预防动脉粥样硬化和纤维化相关肾脏疾病的潜在治疗策略。
