title: AMPK-NF-κB axis in the photoreceptor disorder during retinal inflammation.
abstract: Recent progress in molecular analysis has revealed the possible involvement of multiple inflammatory signaling pathways in pathogenesis of retinal degeneration. However, how aberrant signaling pathways cause tissue damage and dysfunction is still being elucidated. Here, we focus on 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), originally recognized as a key regulator of energy homeostasis. AMPK is also modulated in response to inflammatory signals, although its functions in inflamed tissue are obscure. We investigated the role of activated AMPK in the retinal neural damage and visual function impairment caused by inflammation. For this purpose, we used a mouse model of lipopolysaccharide-induced inflammation in the retina, and examined the effects of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). During inflammation, activated AMPK in the neural retina was decreased, but AICAR treatment prevented this change. Moreover, the electroretinogram (ERG) a-wave response, representing photoreceptor function, showed visual dysfunction in this model that was prevented by AICAR. Consistently, the model showed shortened photoreceptor outer segments (OSs) with reduced levels of rhodopsin, a visual pigment concentrated in the OSs, in a post-transcriptional manner, and these effects were also prevented by AICAR. In parallel, the level of activated NF-κB increased in the retina during inflammation, and this increase was suppressed by AICAR. Treatment with an NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) preserved the rhodopsin level during inflammation, suppressing NF-κB. These findings indicated that AMPK activation by AICAR and subsequent NF-κB inhibition had a protective effect on visual function, and that AMPK activation played a neuroprotective role during retinal inflammation.
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kamoshita
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kubota
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyake
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Chiduru
authors.initials: C
authors.lastname: Tsuda
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nagai
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Yuki
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Shimmura
authors.affiliation: Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004596:Electroretinography; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010786:Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism*; D012164:Retinal Diseases / Q000378:metabolism*; D012243:Rhodopsin / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D012243:Rhodopsin; D000263:Adenylate Kinase; C031143:AICA ribonucleotide