The Renin-Angiotensin System Regulates Neurodegeneration in a Mouse Model of Optic Neuritis.

The major role of the renin-angiotensin system (RAS), including that of angiotensin II (Ang II), the principal effector molecule, in the cardiovascular system is well known. Increasing evidence suggests that the RAS also plays a role in the development of autoimmune diseases. Optic neuritis (ie, inflammation of the optic nerve, with retinal ganglion cell loss) is strongly associated with multiple sclerosis. We investigated the effects of candesartan, an Ang II receptor antagonist, on optic neuritis in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The Ang II concentration was increased in the early phase of EAE. Oral administration of candesartan markedly attenuated demyelination of the optic nerve and spinal cord and reduced retinal ganglion cell loss and visual impairment in mice with EAE. In vitro analyses revealed that Ang II up-regulated the expression of Toll-like receptor (TLR)-4 in astrocytes via the NF-κB pathway. In addition, Ang II treatment enhanced lipopolysaccharide-induced production of monocyte chemoattractant protein 1 in astrocytes, and pretreatment with candesartan or SN50, an NF-κB inhibitor, suppressed the effects of Ang II. The novel pathway of RAS-NF-κB-TLR4 in glial cells identified in the present study may be a valid therapeutic target for neurodegeneration in neuroinflammatory diseases.