Journal Article

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

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

2024

Overview

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.

• Publisher: Springer US,Springer Nature B.V
• Subject: ACE2 / Angiotensin / Angiotensin II - metabolism / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - metabolism / Animals / Apoptosis / Biomedical and Life Sciences / Biomedicine / Cecum / Cell Biology / Encephalopathy / Immunoblotting / Inflammation / Inflammation - metabolism / Inflammation - pathology / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Myeloid cells / Neurobiology / Neurology / Neurons - metabolism / Neurons - pathology / Neuroprotection / Neurosciences / NF-E2-Related Factor 2 - metabolism / Original Article / Oxidative stress / Oxidative Stress - physiology / Peptidyl-dipeptidase A / Protein deficiency / Sepsis / Sepsis - complications / Sepsis - metabolism / Sepsis - pathology / Sepsis-Associated Encephalopathy - metabolism / Sepsis-Associated Encephalopathy - pathology / Signal Transduction