Abstract
The renin angiotensin system (RAS), which is classically known for blood pressure regulation, has functions beyond this. There are two axes of RAS that work to counterbalance each other and are active throughout the body, including the CNS. The pathological axis, consisting of angiotensin II (A1-8), angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT1R), is upregulated in many CNS diseases, including multiple sclerosis (MS). MS is an autoimmune and neurodegenerative disease of the CNS characterized by inflammation, demyelination and axonal degeneration. Published research has described increased expression of AT1R and ACE in tissues from MS patients and in animal models of MS such as experimental autoimmune encephalomyelitis (EAE). In contrast to the pathological axis, little is known about the protective axes of RAS in MS and EAE. In other neurological conditions the protective axis, which includes A1–7, ACE2, angiotensin II type 2 receptor and Mas receptor, has been shown to have anti-inflammatory, regenerative and neuroprotective effects. Here we show, for the first time, changes in the protective arm of RAS in both EAE and MS CNS tissue. We observed a significant increase in expression of the protective arm during stages of disease stabilization in EAE, and in MS tissue showing evidence of remyelination. These data provide evidence that the protective arm of RAS, through both ligand and receptor expression, is associated with reductions in the pathological processes that occur in the earlier stages of MS and EAE, possibly slowing the neurodegenerative process and enhancing neural repair.
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Acknowledgements
This work was supported by the Department of Defense (Grant No. MS130053 – BTL). MS brain specimens were obtained from the Human Brain and Spinal Fluid Resource Center, which is sponsored by NINDS/NIMH, National Multiple Sclerosis Society, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd. Los Angeles, CA 90073, and Veterans Health Services and Research Administration, Department of Veterans Affairs.
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This work was supported by the Department of Defense (Grant No. MS130053 - BTL).
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This animal study was performed in accordance with ethical and humane standards set forth by the National Institutes of Health, and with the approval of University of Southern California’s Institutional Animal Care and Use Committee.
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All of the authors of this manuscript declare no conflict of interest. Dr. Lund has however received investigator-initiated funding from Teva Pharmaceutical Industries, Novartis Pharmaceuticals Corporation and Sanofi-Genzyme for projects unrelated to this work. Dr. Lund has also received honoraria from Teva for projects unrelated to this work. Dr. Kelland has received investigator-initiated funding from Teva Pharmaceutical Industries and Novartis Pharmaceuticals Corporation for projects unrelated to this work. Drs. Rodgers, Stone, Liu, Levy, Kashani and Louie have no industry related conflicts regarding research in multiple sclerosis. Drs. Lund, Kelland, Louie and Rodgers are inventors of U.S. Patent No. 9,623,084.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in these studies involving animals were in accordance with ethical and humane standards set forth by the National Institutes of Health, and with the approval of University of Southern California’s Institutional Animal Care and Use Committee. This article does not contain any studies with human participants performed by any of the authors.
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Stone, R.E., Liu, S., Levy, A.M. et al. Activation of the Protective Arm of the Renin Angiotensin System in Demyelinating Disease. J Neuroimmune Pharmacol 15, 249–263 (2020). https://doi.org/10.1007/s11481-019-09894-7
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DOI: https://doi.org/10.1007/s11481-019-09894-7