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ACE2 agonist DIZE alleviates lung injury induced by limb ischemia-reperfusion in mice

LI Shu-Min^1,2,3, WANG Xiao-Ying¹, LIU Fan¹, YANG Xiu-Hong^1,2,3,*

¹Physiology Department, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China；²Hebei Key Laboratory for Chronic Diseases, Tangshan 063210, China；³Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, Tangshan 063210, China

Abstract

This study was aimed to explore the effect of angiotensin converting enzyme 2 (ACE2) agonist diminazene aceturate (DIZE) on acute lung injury (ALI) induced by limb ischemia-reperfusion (LIR) in mice. Male 8-week-old wild-type and hACE2 transgenic ICR mice were randomly divided into 6 groups (6 in each group), including wild-type control (W), wild-type model (WL), wild-type model with DIZE administration (WLD), transgenic control (T), transgenic model (TL), and transgenic model with DIZE administration (TLD) groups. LIR model was established by 4 h reperfusion following 2 h ischemia of bilateral hindlimbs with rubber bands in mice. The WLD and TLD groups were pretreated with DIZE (15 mg/kg, i.p.) for 4 weeks before LIR. At the end of LIR, the mice were sacrificed and lung tissues were sampled. Indexes for evaluating lung injury include organ coefficient and wet/dry weight ratio (W/D), cell count and protein concentration of bronchoalveolar lavage fluid (BALF), as well as morphological change and pathological score were detected. Angiotensin II (Ang II) and Ang (1-7) levels in lung tissue were determined by using ELISA commercial kits. And the protein expressions of angiotensin II type 1 receptor (AT1) and Mas receptor protein in lung tissue were detected by Western blot. The results were as follows: (1) There was obvious lung injury in both the WL and TL groups. The lung injury in the TL group was lighter than that in the WL group. DIZE could attenuate the lung injury in both the two groups. (2) The WL group showed increased Ang II and decreased Ang (1-7) levels, whereas the TL group did not exhibit any changes of these two proteins. DIZE decreased the level of Ang II in both the WL and TL groups, and increased the level of Ang (1-7) in the WL group. (3) In the WL and TL groups, AT1 and Mas receptor protein expressions were up-regulated. DIZE reversed the change of AT1 protein expression, whereas further increased Mas receptor expression in both the two groups. These results suggest that DIZE may improve the renin-angiotensin system homeostasis by regulating ACE2-Ang (1-7)-Mas axis in local lung tissue and play a protective role in LIR-induced ALI in mice.

Key words: ischemia and reperfusion; lung injury; renin-angiotensin system; angiotensin-converting enzyme; angiotensin converting enzyme 2; diminazene aceturate

Received: 2017-08-19　　Accepted: 2018-03-29

Corresponding author: 杨秀红　　E-mail: ljkyxhljn@163.com

DOI: 10.13294/j.aps.2018.0029

Citing This Article：

LI Shu-Min, WANG Xiao-Ying, LIU Fan, YANG Xiu-Hong. ACE2 agonist DIZE alleviates lung injury induced by limb ischemia-reperfusion in mice. Acta Physiol Sin 2018; 70 (2): 175-183 (in Chinese with English abstract).