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ACE2 Rescues Sepsis-Associated Encephalopathy by Reducing Inflammation, Oxidative Stress, and Neuronal Apoptosis via the Nrf2/Sestrin2 Signaling Pathway

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Abstract

Neuroinflammation and oxidative stress contribute to the progression of sepsis-associated encephalopathy (SAE). Angiotensin-converting enzyme 2 (ACE2) is considered to be a neuroprotective factor due to its anti-inflammatory and antioxidant properties. However, the role of ACE2 on myeloid cells in regulating SAE and the underlying mechanism warrants further exploration. SAE was induced in ACE2 transgenic (TG), knockout (KO), and bone marrow (BM) chimeric mice by cecal ligation and puncture (CLP). The expression levels of apoptosis-, oxidation- and neuroinflammation-associated mediators and morphological changes were monitored by quantitative real-time PCR analyses and histological examinations in the cortex of septic mice. The contents of angiotensin (Ang) II and Ang-(1–7) along with the activity of ACE2 were examined with commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2 was detected by immunoblotting analysis. Our results indicated that the expression of cortical ACE2 was significantly reduced in the early phase of CLP-induced sepsis. Moreover, ACE2 overexpression in TG mice conferred neuroprotection against sepsis, as evidenced by alleviated neuronal apoptosis, oxidative stress, and proinflammatory M1-like microglial polarization, accompanied by upregulation of the Ang-(1–7), Nrf2, and Sestrin2 protein levels. Conversely, ACE2 deficiency in KO mice exacerbated SAE. The neuroprotective effects of ACE2 were further confirmed in wild-type mice transplanted with ACE2-TG and KO BM cells. Therefore, our data suggest that myeloid ACE2 exerts a protective role in the pathogenesis of SAE, potentially by activating Ang-(1–7)-Nrf2/sestrin2 signaling pathway, and highlight that upregulating ACE2 expression and activity may represent a promising approach for the treatment of SAE in patients with sepsis.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ACE2:

Angiotensin-converting enzyme 2

Ang-II:

Angiotensin II

Ang-(1–7):

Angiotensin-(1–7)

Arg-1:

Arginase-1

Bax:

BCL-2-associated X protein

BCL-2:

B-cell lymphoma-2

BMT:

Bone marrow transplantation

BSA:

Bovine serum albumin

CLP:

Cecal ligation and puncture

CNS:

Central nervous system

DAPI:

4′,6-Diamidino-2-phenylindole

DHE:

Dihydroethidium

ELISA:

Enzyme-linked immunosorbent assay

IL-1β:

Interleukin 1β

IL-6:

Interleukin 6

KO:

Knockout

MasRs:

Mas receptors

NLRP3:

NOD-like receptor thermal protein domain associated protein 3

NOX:

NADPH oxidase

Nrf2:

Nuclear factor erythroid 2-related factor 2

PBS:

Phosphate buffer solution

RAS:

Renin-angiotensin system

ROS:

Reactive oxygen species

SAE:

Sepsis-associated encephalopathy

TG:

Transgenic

TNF-α:

Tumor necrosis factor alpha

TUNEL:

Terminal-deoxynucleotidyl transferase-mediated nick end labeling

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Funding

This work was supported by the National Naturel Science Foundation of China (grant number 82172123) to Shubin Guo.

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Authors and Affiliations

  1. Emergency Medicine Clinical Research Center, Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China

    Ya Li, Tian-Tian Wan, Jia-Xin Li, Xue Xiao, Lei Liu, Hui-Hua Li & Shu-Bin Guo

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  1. Ya Li
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Contributions

Ya Li, Tian-Tian Wan, Jia-Xin Li, Xue Xiao, and Lei Liu performed the experiments. Ya Li conducted data collection, statistical analysis, and interpretation. Hui-Hua Li and Ya Li designed the experiments and prepared the manuscript. Hui-Hua Li and Shu-Bin Guo were responsible for the supervision of the project. Shubin Guo offered funding support. All authors read and approved the final manuscript.

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Correspondence to Hui-Hua Li or Shu-Bin Guo.

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The protocols of this study were approved by Animal Care and Use Committee of Beijing Chaoyang Hospital of Capital Medical University (approval number 2021-Animal-35, February 26, 2021), and all experiments were carried out by following the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

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Li, Y., Wan, TT., Li, JX. et al. ACE2 Rescues Sepsis-Associated Encephalopathy by Reducing Inflammation, Oxidative Stress, and Neuronal Apoptosis via the Nrf2/Sestrin2 Signaling Pathway. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04063-1

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