Aqp9 Gene Deletion Enhances Retinal Ganglion Cell (RGC) Death and Dysfunction Induced by Optic Nerve Crush: Evidence tha
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Aqp9 Gene Deletion Enhances Retinal Ganglion Cell (RGC) Death and Dysfunction Induced by Optic Nerve Crush: Evidence that Aquaporin 9 Acts as an Astrocyte-to-Neuron Lactate Shuttle in Concert with Monocarboxylate Transporters To Support RGC Function and Survival Sotaro Mori 1 & Takuji Kurimoto 1 & Akiko Miki 1 & Hidetaka Maeda 2 & Sentaro Kusuhara 1 & Makoto Nakamura 1 Received: 9 February 2020 / Accepted: 22 July 2020 # The Author(s) 2020
Abstract Aquaporin 9 (AQP9) is an aquaglyceroporin that can transport lactate. Accumulating evidence suggests that astrocyte-to-neuron lactate shuttle (ANLS) plays a critical role in energy metabolism in neurons, including retinal ganglion cells (RGCs). To test the hypothesis that AQP9, in concert with monocarboxylate transporters (MCTs), participates in ANLS to maintain function and survival of RGCs, Aqp9-null mice and wild-type (WT) littermates were subjected to optic nerve crush (ONC) with or without intravitreal injection of an MCT2 inhibitor. RGC density was similar between the Aqp9-null mice and WT mice without ONC, while ONC resulted in significantly more RGC density reduction in the Aqp9-null mice than in the WT mice at day 7. Positive scotopic threshold response (pSTR) amplitude values were similar between the two groups without ONC, but were significantly more reduced in the Aqp9-null mice than in the WT mice 7days after ONC. MCT2 inhibitor injection accelerated RGC death and pSTR amplitude reduction only in the WT mice with ONC. Immunolabeling revealed that both RGCs and astrocytes expressed AQP9, that ONC predominantly reduced astrocytic AQP9 expression, and that MCTs 1, 2, and 4 were co-localized with AQP9 at the ganglion cell layer. These retinal MCTs were also co-immunoprecipitated with AQP9 in the WT mice. ONC decreased the co-immunoprecipitation of MCTs 1 and 4, but did not impact co-immunoprecipitation of MCT2. Retinal glucose transporter 1 expression was increased in Aqp9-null mice. Aqp9 gene deletion reduced and increased the intraretinal L-lactate and D-glucose concentrations, respectively. Results suggest that AQP9 acts as the ANLS to maintain function and survival of RGCs. Keywords Aquaporin 9 . Monocarboxylate transporter . Astrocyte-to-neuron lactate shuttle . Optic nerve crush . Retinal ganglion cells . Scotopic threshold response
Abbreviations ANLS Astrocyte-to-neuron lactate shuttle ANOVA One- or two-way analysis of variance AQP9 Aquaporin 9 DAPI 4′,6-Diamidino-2-phenylindole A part of this study was presented at The Association for Research in Vision and Ophthalmology meetings held in Vancouver, Canada, 2019. * Makoto Nakamura [email protected] 1
Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
2
Maeda Eye Clinic, 1-1-1, Uchihonmachi, Chuo-ku, Osaka 540-0012, Japan
ERG FG GCL Gapdh GFAP GLUT INL IOP IPL IR KO MCT nSTR ONC ONL OPL
Electroretinogram FluoroGold Ganglion cell layer Glyceraldehyde 3-phosphate dehydrogenase Glial fibrillary acidic
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