Pharmacological Blockade of Aquaporin-4 Attenuates Na⁺/K⁺-ATPase Dysfunction-Induced Inner Retinal Injury in Rats
Abstract
Diabetic retinopathy, a major cause of visual impairment, involves multiple pathological processes, including disruption of water homeostasis regulated by Müller glial cells. Aquaporin-4 (AQP4) is a water channel that mediates passive water transport driven by an osmotic gradient, whereas Na+/K+-ATPase (NKA) maintains the ionic balance underlying this process. We previously demonstrated that ouabain, an NKA inhibitor, preferentially induces neuronal cell loss in the inner retina. This study aimed to elucidate the role of AQP4 in ouabain-induced inner retinal injury using male Sprague–Dawley rats and rat retinal Müller cells (rMC-1). Immunohistochemical analysis revealed that AQP4 was localized to the endfeet of Müller cells along the deep retinal capillaries and was expressed throughout the cell body in rMC-1 cells. To assess the role of AQP4 in ouabain-induced retinal injury, we examined the effects of TGN020, an AQP4 inhibitor, using both in vitro and in vivo models. Ouabain induced acute cell swelling in rMC-1 cells, and this effect was significantly attenuated by TGN020 treatment. In vivo, rats were intravitreally injected with ouabain alone or in combination with TGN020, and retinal histological changes were evaluated 7 d after injection. Ouabain induced cell loss in both the ganglion cell layer (GCL) and inner nuclear layer (INL). Co-administration of TGN020 reduced cell loss in the INL, but not in the GCL. These findings suggest that the disruption of AQP4-mediated water transport in Müller cells may contribute to INL neurodegeneration associated with NKA dysfunction in rats.
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BibTeX
@article{odaka2026pharmacological,
title = {{Pharmacological Blockade of Aquaporin-4 Attenuates Na⁺/K⁺-ATPase Dysfunction-Induced Inner Retinal Injury in Rats}},
author = {Ryosuke Odaka and Saori Deguchi and Akane Morita and Toshihide Kashihara and Tsutomu Nakahara},
journal = {Biological and Pharmaceutical Bulletin},
year = {2026},
month = aug,
doi = {10.1248/bpb.b26-00314},
url = {https://www.jstage.jst.go.jp/article/bpb/49/8/49_b26-00314/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Pharmacological Blockade of Aquaporin-4 Attenuates Na⁺/K⁺-ATPase Dysfunction-Induced Inner Retinal Injury in Rats
AU - Ryosuke Odaka
AU - Saori Deguchi
AU - Akane Morita
AU - Toshihide Kashihara
AU - Tsutomu Nakahara
PY - 2026
DA - 2026/08/28
JO - Biological and Pharmaceutical Bulletin
DO - 10.1248/bpb.b26-00314
UR - https://www.jstage.jst.go.jp/article/bpb/49/8/49_b26-00314/_article
AB - Diabetic retinopathy, a major cause of visual impairment, involves multiple pathological processes, including disruption of water homeostasis regulated by Müller glial cells. Aquaporin-4 (AQP4) is a water channel that mediates passive water transport driven by an osmotic gradient, whereas Na+/K+-ATPase (NKA) maintains the ionic balance underlying this process. We previously demonstrated that ouabain, an NKA inhibitor, preferentially induces neuronal cell loss in the inner retina. This study aimed to elucidate the role of AQP4 in ouabain-induced inner retinal injury using male Sprague–Dawley rats and rat retinal Müller cells (rMC-1). Immunohistochemical analysis revealed that AQP4 was localized to the endfeet of Müller cells along the deep retinal capillaries and was expressed throughout the cell body in rMC-1 cells. To assess the role of AQP4 in ouabain-induced retinal injury, we examined the effects of TGN020, an AQP4 inhibitor, using both in vitro and in vivo models. Ouabain induced acute cell swelling in rMC-1 cells, and this effect was significantly attenuated by TGN020 treatment. In vivo, rats were intravitreally injected with ouabain alone or in combination with TGN020, and retinal histological changes were evaluated 7 d after injection. Ouabain induced cell loss in both the ganglion cell layer (GCL) and inner nuclear layer (INL). Co-administration of TGN020 reduced cell loss in the INL, but not in the GCL. These findings suggest that the disruption of AQP4-mediated water transport in Müller cells may contribute to INL neurodegeneration associated with NKA dysfunction in rats.
SN - 1347-5215
SN - 0918-6158
ER -