title: Renin-angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma.
abstract: Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs, and the loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP). In the present study, we found that expressions of angiotensin II type 1 receptor (AT1-R) and Toll-like receptor 4 (TLR4) are increased in RGCs and retinal Müller glia in EAAC1-deficient (KO) mice. The orally active AT1-R antagonist candesartan suppressed TLR4 and lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expressions in the EAAC1 KO mouse retina. Sequential in vivo retinal imaging and electrophysiological analysis revealed that treatment with candesartan was effective for RGC protection in EAAC1 KO mice without affecting IOP. In cultured Müller glia, candesartan suppressed LPS-induced iNOS production by inhibiting the TLR4-apoptosis signal-regulating kinase 1 pathway. These results suggest that the renin-angiotensin system is involved in the innate immune responses in both neural and glial cells, which accelerate neural cell death. Our findings raise intriguing possibilities for the management of glaucoma by utilizing widely prescribed drugs for the treatment of high blood pressure, in combination with conventional treatments to lower IOP.
authors.affiliation: 1] Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [2] Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Semba
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Namekata
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.affiliation: Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Harada
authors.affiliation: 1] Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [2] Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Mitamura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D050580:Excitatory Amino Acid Transporter 3 / Q000172:deficiency / Q000235:genetics; D005901:Glaucoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D012084:Renin-Angiotensin System; D012160:Retina / Q000201:enzymology / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D050580:Excitatory Amino Acid Transporter 3; C493399:Slc1a1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4