ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway - PubMed (original) (raw)

ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway

Rensong Ye et al. Exp Mol Pathol. 2020 Apr.

Abstract

This study aimed to investigate the protective effect of angiotensin converting enzyme 2 (ACE2) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). After generating ALI mouse models by injecting LPS, the levels of ACE2, inflammatory factors, and downstream proteins of the LPS-TLR4 pathway were analyzed. LPS-challenged BEAS-2B cells were established in vitro. Next, a eukaryotic expression vector, pm-ACE2, was constructed and validated. Challenged cells were transfected with pm-ACE2 containing enhanced green fluorescent protein, or they were treated with D-Ala-Ang-(1-7), angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB) and the LPS-TLR4 pathway inhibitor dimethyl fumarate (DMF) for analysis of how the above factors contribute to ACE2 regulation. Expression of renin, Ang II, ACE and angiotensin II type 1 receptor (AT1R) was subsequently assessed. In the ALI model, mice exhibited decreased expression of ACE2, lung pathological injury, inflammatory injury, and abnormal activation of the LPS-TLR4 pathway. LPS-challenged BEAS-2B cells demonstrated upregulated expression of renin, Ang II, ACE and AT1R. After injection of ACE2, lung function and lung pathological injury were significantly improved, and that effect was accompanied by attenuated inflammation, and inactivation of the LPS-TLR4 pathway. Cell studies showed similar results. The above observations were further enhanced when there was a combined treatment with DMF and pm-ACE2. D-Ala-Ang-(1-7) treatment attenuated the protective effect of ACE2, while ACEI and ARB treatment alleviated LPS-induced pneumonic injury. In conclusion, ACE2 was expressed at low levels in response to LPS-induced ALI. Overexpression of ACE2 regulates the ACE2/Ang-(1-7)/Mas and ACE/Ang II/AT1 axes to maintain dynamic balance of the renin-angiotensin system, and attenuate inflammatory response.

Keywords: ACE/Ang II/AT1 axis; ACE2/Ang-(1–7)/mas axis; Acute lung injury; Angiotensin converting enzyme 2; LPS-TLR4 pathway; Lipopolysaccharide; Renin-angiotensin systems.

Copyright © 2020 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that there are no conflicts of interest.

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