Angiotensin II Type 1 Receptor Signaling Drives Pro-Inflammatory and Oxidative Microglial Responses
Description
Background: Microglial-mediated neuroinflammation is a central pathological process across a range of central nervous system (CNS) disorders, including autoimmune neuroinflammatory conditions such as multiple sclerosis (MS). The renin-angiotensin-aldosterone system (RAAS), acting through angiotensin II (Ang II) and the angiotensin II type 1 receptor (AT1R), modulates CNS immune function, but the direct effects of Ang II-AT1R signaling on microglial inflammatory and oxidative responses remain poorly defined. Methods: RAAS component expression was examined in brain tissue from experimental autoimmune encephalomyelitis (EAE) and control mice (n=6 per group) by quantitative real-time PCR. Human HMC3 microglial cells were treated with Ang II (10 or 100 nM) with or without the selective AT1R antagonist losartan (1 μM) for 24 h. Inflammatory mediators (IL-6, iNOS, NF-κB) were assessed by qRT-PCR, ELISA, and a phospho-p65 assay; reactive oxygen species (ROS) by flow cytometry; and nitric oxide by Griess assay. Results: EAE brain tissue showed elevated angiotensinogen, AT1R, and inducible nitric oxide synthase (iNOS) expression versus controls, with no change in AT2R. In HMC3 cells, Ang II dose-dependently increased IL-6 expression and secretion, iNOS expression and nitric oxide production, ROS generation, and NF-κB activation. Losartan attenuated all Ang II-induced responses, reducing IL-6 secretion by >80%, normalizing iNOS and nitrite levels, and decreasing ROS-positive cells from ~46% to ~19%. Conclusions: Ang II-AT1R signaling promotes a pro-inflammatory, pro-oxidative microglial phenotype, and losartan consistently reverses these effects, supporting AT1R as a mechanistically relevant therapeutic target in neuroinflammatory disorders.
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Institutions
- San Juan Bautista School of MedicineCaguas, Caguas