2. Academic Validation
  3. TRPV4 channels promote vascular permeability in retinal vascular disease

TRPV4 channels promote vascular permeability in retinal vascular disease

  • Exp Eye Res. 2023 Feb 9;109405. doi: 10.1016/j.exer.2023.109405.
Anri Nishinaka 1,  Miruto Tanaka 1,  Kentaro Ohara 2,  Eiji Sugaru 2,  Yuji Shishido 2,  Akemi Sugiura 2,  Yukiko Moriguchi 2,  Amane Toui 2,  Shinsuke Nakamura 1,  Kaoru Shimada 3,  Shuzo Watanabe 4,  Hideaki Hara 5,  Masamitsu Shimazawa 6
Affiliations

Affiliations

  • 1 Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
  • 2 RaQualia, Pharma Inc., Nagoya, Japan; RaQualia Pharma Industry-Academia Collaborative Research Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
  • 3 RaQualia, Pharma Inc., Nagoya, Japan; Laboratory of Collaborative Research for Innovative Drug Discovery, Gifu Pharmaceutical University, Gifu, Japan.
  • 4 RaQualia, Pharma Inc., Nagoya, Japan.
  • 5 Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan; Laboratory of Collaborative Research for Innovative Drug Discovery, Gifu Pharmaceutical University, Gifu, Japan.
  • 6 Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan; Laboratory of Collaborative Research for Innovative Drug Discovery, Gifu Pharmaceutical University, Gifu, Japan. Electronic address: shimazawa@gifu-pu.ac.jp.
PMID: 36773739 DOI: 10.1016/j.exer.2023.109405
Abstract

This study aimed to determine the role of transient receptor potential vanilloid 4 (TRPV4), a calcium (CA2+)-permeable cation channel, in the pathophysiology of retinal vascular disease. The retinal vein occlusion (RVO) murine model was created by irradiating retinal veins using lasers. TRPV4 expression and localization were evaluated in RVO mice retinas. In addition, we examined the effects of TRPV4 antagonists (RQ-00317310, HC-067047, GSK2193874, and GSK2798745) on retinal edema, blood flow, and ischemic areas in RVO mice. Furthermore, changes in the retinal expression of tumor necrosis factor (TNF)-α and aquaporin4 (AQP4) by RQ-00317310 were analyzed using western blot. We also assessed the barrier integrity of epithelial cell monolayers using trans-endothelial electrical resistance (TEER) in Human Retinal Microvascular Endothelial Cells (HRMECs). The expression of TRPV4 was significantly increased and co-localized with glutamine synthetase (GS), a Müller glial marker, in the ganglion cell layer (GCL) of the RVO mice. Moreover, RQ-00317310 administration ameliorated the development of retinal edema and ischemia in RVO mice. In addition, the up regulation of TNF-α and down-regulation of AQP4 were lessened by the treatment with RQ-00317310. Treatment with GSK1016790A, a TRPV4 agonist, increased vascular permeability, while RQ-00317310 treatment decreased vascular endothelial growth factor (VEGF)- or TRPV4-induced retinal vascular hyperpermeability in HRMECs. These findings suggest that TRPV4 plays a role in the development of retinal edema and ischemia. Thus, TRPV4 could be a new therapeutic target against the pathological symptoms of retinal vascular diseases.

Keywords

AQP4; Retinal edema; Retinal vein occlusion; TRPV4; VEGF; Vascular permeability.

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