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.
Highlights
Accumulating evidence indicates that some neurons in the central nervous system prefer lactate over glucose as an energy substrate and that astrocyte-to-neuron lactate shuttle (ANLS) plays a critical role in maintaining neuronal metabolism, function, and survival [1, 2]
Retinas obtained 7 days after optic nerve crush (ONC) were subjected to immunoblotting, which demonstrated that ONC decreased Aquaporin 9 (AQP9) protein expression by approximately 40% (n = 3, p < 0.01, unpaired t test; Fig. 2b, d)
Unlike the WT mice, ONC did not reduce the total retinal MCT1 levels in the Aqp9 KO mice (Fig. 3e, f). These results suggest that MCT1 molecules that do not interact with AQP9 exist, that their expression levels are upregulated in Aqp9 KO mice under physiological conditions to possibly compensate for lowered availability of AQP9, and that upregulated MCT1 expression irrelevant to the AQP9 expression is unchanged after ONC in these mice
Summary
Accumulating evidence indicates that some neurons in the central nervous system prefer lactate over glucose as an energy substrate and that astrocyte-to-neuron lactate shuttle (ANLS) plays a critical role in maintaining neuronal metabolism, function, and survival [1, 2]. It has been reported that elevated intraocular pressure (IOP) and optic nerve transection in rodents [11, 12], and glaucoma in humans [13], lead to reduced AQP9 expression in RGCs. Further, we previously demonstrated that AQP9 expression is required for L-lactate to maintain survival of RGCs in culture [14]. We previously demonstrated that AQP9 expression is required for L-lactate to maintain survival of RGCs in culture [14] These lines of evidence implicate AQP9 as a lactate transporter in ANLS in the inner retina
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
