Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice.
Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice.
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DOI：
10.1002/hep.23104
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发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Brenner DA
中科院分区：
文献类型：
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作者：
Osterreicher CH;Taura K;De Minicis S;Seki E;Penz-Osterreicher M;Kodama Y;Kluwe J;Schuster M;Oudit GY;Penninger JM;Brenner DA
肾素-血管紧张素系统（RAS）在肝纤维化中起主要作用。最近，血管紧张素转换酶1（ACE 1）的同源物，称为ACE 2，已被确定，似乎是一个负调节的RAS通过降解血管紧张素II为血管紧张素1 -7。本研究的目的是描述肝脏中ACE 2基因缺失的长期影响，确定ACE 2在急性和慢性肝病中的作用，并描述Ang 1 -7在肝星状细胞（HSC）活化中的作用。Ace 2基因敲除（KO）小鼠和野生型（wt）同窝仔经历了不同的急性和慢性肝损伤模型。通过组织学、免疫组织化学、α平滑肌肌动蛋白（α-SMA）免疫印迹和定量聚合酶链反应（qPCR）分析肝脏病理学。采用胶原酶-链霉蛋白酶灌注法和密度梯度离心法分离小鼠HSC。一岁大的ace 2基因敲除小鼠自发出现炎性细胞浸润和轻度肝纤维化，厄贝沙坦治疗可以预防。Ace 2 KO小鼠在胆管结扎21天或慢性四氯化碳（CCl 4）治疗后显示肝纤维化增加。相比之下，ace 2 KO小鼠急性肝损伤模型没有不同的野生型同窝出生。在胆汁淤积性和中毒性肝损伤过程中，用重组ACE 2治疗减轻了实验性纤维化。HSC表达Ang 1 -7受体Mas，Ang 1 -7抑制培养的HSC中Ang II诱导的细胞外信号调节激酶（ERK）-1/2磷酸化。ACE 2是RAS的关键负调节因子，其作用是通过Ang II的降解和Ang 1 -7的形成来限制纤维化。在慢性肝损伤模型中，ACE 2活性的丧失导致肝纤维化，而给予重组ACE 2显示出治疗潜力。
The renin-angiotensin system (RAS) plays a major role in liver fibrosis. Recently, a homolog of angiotensin-converting-enzyme 1 (ACE1), termed ACE2, has been identified that appears to be a negative regulator of the RAS by degrading Ang II to Ang1–7. The aim of this study was to characterize the long-term effects of gene deletion of ACE2 in the liver, to define the role of ACE2 in acute and chronic liver disease, and to characterize the role of Ang1–7 in hepatic stellate cell (HSC) activation. Ace2 knockout (KO) mice and wild-type (wt) littermates underwent different models of acute and chronic liver injury. Liver pathology was analyzed by histology, immunohistochemistry, alpha smooth muscle actin (α-SMA) immunoblotting, and quantitative polymerase chain reaction (qPCR). Murine HSCs were isolated by collagenase-pronase-perfusion, and density gradient centrifugation. One-year-old ace2 KO mice spontaneously developed an inflammatory cell infiltration and mild hepatic fibrosis that was prevented by treatment with irbesartan. Ace2 KO mice showed increased liver fibrosis following bile duct ligation for 21 days or chronic carbon tetrachloride (CCl4) treatment. In contrast, ace2 KO mice subjected to acute liver injury models did not differ from wt littermates. Treatment with recombinant ACE2 attenuated experimental fibrosis in the course of cholestatic and toxic liver injury. HSCs express the Ang1–7 receptor Mas and Ang1–7 inhibited Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 in cultured HSCs. ACE2 is a key negative regulator of the RAS and functions to limit fibrosis through the degradation of Ang II and the formation of Ang1–7. Whereas loss of ACE2 activity worsens liver fibrosis in chronic liver injury models, administration of recombinant ACE2 shows therapeutic potential.