DOI: 10.25549/usctheses-c40-315536
title: The role of the renin angiotensin system in models of demyelinating disease: a potential target for progressive multiple sclerosis

description: Multiple Sclerosis (MS) is an autoimmune and neurodegenerative disease of the CNS characterized by inflammation, demyelination, and axonal degeneration. The pathological arm of the renin angiotensin system (RAS), which consists of angiotensin II (Ang II), angiotensin converting enzyme (ACE), and the angiotensin II type 1 receptor (AT1R), is known to be upregulated both in tissues from MS patients, and in the experimental autoimmune encephalomyelitis (EAE) models of autoimmune-mediated demyelination. Furthermore, perturbation of the pathological arm of RAS is also associated with other CNS disease states such as ischemic stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, schizophrenia and bipolar disorder. In contrast, little is known of changes in the protective arm of RAS, which includes angiotensin 1-7 (A(1-7)), ACE2, and Mas receptor (MasR), in MS and its disease models. In other non-MS studies, the A(1-7)/ACE2/MasR axis counteracts the deleterious effects of the pathological RAS arm leading to anti-inflammatory, regenerative and neuroprotective effects. As these actions target aspects of disease pathology in neurodegeneration, it suggests that the protective arm could provide benefit in a neurological disease, such as MS. In this dissertation report, using both tissues from an EAE model and CNS tissue from MS patients, we show for the first time significant changes in the protective arm of RAS in demyelinating disease course. During the course of EAE and in MS brain tissue we observed a significant increase in MasR expression over time. Furthermore, there were marked fluctuations in the levels of A(1-7) in the CNS; the peptide only increased in the late stages of disease when clinical symptoms plateaued, whereas the pathological arm metabolite, AngII increased early in disease when clinical onset began. These data provide evidence that the protective arm of RAS, through endogenous ligand and receptor expression, responds to the pathological processes that occur in MS and its animal model EAE. Furthermore, based on pathology and the timing of the upregulation in MasR expression, we believe this occurs in response to injury and may slow the process of neurodegeneration. ❧ While the etiology of MS is not yet known, immunomodulatory therapies have been somewhat effective at reducing the frequency and severity of relapses in RR-MS. Still, the disease can progress in some patients into a secondary progressive phase, in which axon loss indicates permanent neurologic disability. Progressive stages of disease are associated with local inflammation and oxidative stress leading to neurodegeneration. Therefore, therapies with local anti-inflammatory and neuroprotective capabilities are needed to treat this stage of disease. In this dissertation report we show that the protective arm of the renin angiotensin system (RAS) is upregulated in the CNS in late stages of demyelinating disease both in MS and in myelin oligodendrocyte glycoprotein (MOG)-EAE, and is associated with remyelination in MS and symptom plateau in MOG-EAE. Based on this discovery, we tested the therapeutic effects of the active metabolite of the protective arm, A(1-7), in MOG-EAE. Based on a dose-response study we found that A(1-7) 1mg/kg/day delivered by osmotic pump and A(1-7) 2mg/kg/day twice daily injections effectively reduced clinical disease severity, demyelination, cellular infiltration and axonal loss in the spinal cord in MOG-EAE mice. A(1-7) 2mg/kg/day twice daily injections effectively reduced oxidative stress as well. A therapy that can target these cornerstones of MS pathology is a necessary component to contemporary MS treatment. ❧ Pathologically, active MS lesions are heterogeneous among MS patients. The inflammatory environment as well as the cellular landscape can differ from patient to patient. While most patients have an inflammatory component, 26% of patients have profound oligodendrocyte apoptosis as well as inflammation. Prevention of oligodendrocyte loss may be an important mechanism to target in MS. A(1-7) is active metabolite of the RAS that has anti-apoptotic and neuroprotective effects, and has shown benefit in the treatment of the adaptive-immune driven demyelinating model, MOG-EAE. In this report we show for the first time A(1-7) administration in a cuprizone induced demyelinating mouse model prevents oligodendrocyte loss, oligodendrocyte apoptosis and preserves myelin integrity. The data presented in this dissertation are novel and significant contributions to the field of MS therapy.