• Blood-Retinal Barrier/physiology
• Blood-Retinal Barrier/metabolism
• Humans
• Transient Receptor Potential Channels/metabolism
• Transient Receptor Potential Channels/physiology
• Animals
• Calcium Signaling
• Calcium/metabolism
• Endothelial Cells/metabolism

• müller glia
• astrocytes
• human retina
• calbindin
• fovea

• Humans
• Ependymoglial Cells/metabolism
• Ependymoglial Cells/cytology
• Aged
• Aged, 80 and over
• Male
• Female
• Fovea Centralis/metabolism
• Fovea Centralis/cytology
• Middle Aged
• Immunohistochemistry
• Adult
• Glial Fibrillary Acidic Protein/metabolism
• Microscopy, Confocal
• Cell Count
• Glutamate-Ammonia Ligase/metabolism
• Carrier Proteins/metabolism

• Animals
• TRPV Cation Channels/antagonists & inhibitors
• TRPV Cation Channels/biosynthesis
• Mice
• Intraocular Pressure/physiology
• Intraocular Pressure/drug effects
• Tomography, Optical Coherence
• Retinal Ganglion Cells/pathology
• Retinal Ganglion Cells/metabolism
• Mice, Inbred C57BL
• Ocular Hypertension/physiopathology
• Ocular Hypertension/metabolism
• Electroretinography
• Disease Models, Animal
• Aging/physiology
• Immunohistochemistry
• Male
• Retina/physiopathology
• Retina/metabolism
• Acute Disease
• Morpholines
• Pyrroles

• BK
• ENaC
• TRAAK
• TRPV2
• TRPV4
• confocal microscopy
• immunocytochemistry
• whole-cell patch-clamp

• P30 EY002520 NEI NIH HHS
• R01 EY033492 NEI NIH HHS

• Glaucoma
• IOP regulation
• K2P channels
• Mechanosensitive ion channels
• Mechanotransduction
• PIEZO channels
• RGC survival
• TRP channels

• Humans
• Ion Channels/physiology
• Intraocular Pressure/physiology
• Mechanotransduction, Cellular/physiology
• Glaucoma/physiopathology
• Retinal Ganglion Cells/physiology
• Transient Receptor Potential Channels/physiology
• Animals

• K08 EY034600 NEI NIH HHS
• P30 EY026877 NEI NIH HHS
• T32 EY027816 NEI NIH HHS

• TRPs channels
• age-related macular degeneration
• diabetic retinopathy
• glaucoma
• retinitis pigmentosa

• ERG
• TRPV4
• confocal microscopy
• immunocytochemistry
• light response
• patch-clamp
• photoreceptor
• rod bipolar cell

• P30 EY002520 NEI NIH HHS
• R01 EY033492 NEI NIH HHS
• T32 EY007001 NEI NIH HHS

• BK
• ENaC
• Piezo
• TRAAK
• TREK
• TRP
• TRPV
• amacrine cell
• bipolar cell
• ganglion cell
• horizontal cell
• mechanical-sensitive ion channels
• photoreceptor
• retina

• Humans
• Animals
• Ion Channels/metabolism
• Retinal Neurons/metabolism
• Mechanotransduction, Cellular
• Retina/metabolism
• Retina/cytology

• Apoptosis
• CaMKII
• Glaucoma
• Retinal ganglion cells
• TRPV4
• Tumor necrosis factor-α

• Rats
• Animals
• Retinal Ganglion Cells/metabolism
• Tumor Necrosis Factor-alpha/metabolism
• Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
• TRPV Cation Channels/metabolism
• Glaucoma/drug therapy
• Ocular Hypertension/drug therapy
• Apoptosis
• Disease Models, Animal

• nanoparticle transducers
• neuromodulation
• optical nanosensors
• retinal degeneration
• retinal pharmacokinetics
• retinal prosthesis

• Glaucoma
• Ocular disease
• Optic nerve damage
• Retinal ganglion cell
• TRPV
• Trabecular meshwork

• Humans
• Glaucoma
• Sclera/pathology
• Retina/pathology
• Trabecular Meshwork/metabolism
• Optic Nerve Injuries/metabolism
• Optic Nerve/pathology

• AQP4
• TRPV4
• astrocytes
• calcium ions
• cell swelling
• ion channels
• water channels

• Apoptosis
• Glaucoma
• Pressure
• Retinal ganglion cells
• TRPV4

• Activation
• Astrocyte
• Glaucoma
• Microglia
• Müller cells
• Retinal ganglion cell degeneration

• electrophysiology
• gold nanorods
• infrared neural modulation
• retina
• retinal ganglion cells
• retinal prosthesis

• Rats
• Animals
• Retinal Ganglion Cells
• Visual Prosthesis
• Light
• Action Potentials/physiology
• Electric Stimulation

• Animals
• Transient Receptor Potential Channels/physiology
• Mechanotransduction, Cellular
• Retina/metabolism
• Drosophila/metabolism
• Homeostasis
• Drosophila Proteins/metabolism

• R01 EY022076 NEI NIH HHS
• UL1 TR002538 NCATS NIH HHS
• R01 EY027920 NEI NIH HHS
• R01 EY031817 NEI NIH HHS
• P30 EY014800 NEI NIH HHS

• Ciliary body
• Cornea
• Eye
• Glaucoma
• Retina
• TRPV4
• Trabecular meshwork

• Animals
• Cornea/metabolism
• Lipids
• Retina
• TRPV Cation Channels/metabolism
• Vertebrates/metabolism

• R01 EY022076 NEI NIH HHS
• UL1 TR002538 NCATS NIH HHS
• R01 EY027920 NEI NIH HHS
• R01 EY031817 NEI NIH HHS
• T32 EY024234 NEI NIH HHS
• P30 EY014800 NEI NIH HHS

The senses of proprioception, touch, hearing, and blood pressure on mechanosensitive ion channels that transduce mechanical stimuli with high sensitivity and speed. This conversion process is usually called mechanotransduction. From nematode MEC-4/10 to mammalian PIEZO1/2, mechanosensitive ion channels have evolved into several protein families that use variant gating models to convert different forms of mechanical force into electrical signals. In addition to the model of channel gating by stretching from lipid bilayers, another potent model is the opening of channels by force tethering: a membrane-bound channel is elastically tethered directly or indirectly between the cytoskeleton and the extracellular molecules, and the tethering molecules convey force to change the channel structure into an activation form. In general, the mechanical stimulation forces the extracellular structure to move relative to the cytoskeleton, deforming the most compliant component in the system that serves as a gating spring. Here we review recent studies focusing on the ion channel mechanically activated by a tethering force, the mechanotransduction-involved cytoskeletal protein, and the extracellular matrix. The mechanosensitive channel PIEZO2, DEG/ENaC family proteins such as acid-sensing ion channels, and transient receptor potential family members such as NompC are discussed. State-of-the-art techniques, such as polydimethylsiloxane indentation, the pillar array, and micropipette-guided ultrasound stimulation, which are beneficial tools for exploring the tether model, are also discussed.

• Atlantic salmon
• TRPV1
• TRPV4
• melatonin
• pineal organ
• temperature
• transient receptor potential vanilloid (TRPV)

• Agence Nationale de la Recherche
• Conseil National de la Recherche Scientifique
• Sorbonne Université

• Blood-retina barrier
• Inflammation
• Neurodegeneration
• Pharmacology
• Retinal circulation
• Retinal endothelial cells
• Retinopathy
• TRP channels

Glaucoma, the leading cause of irreversible blindness worldwide, is a type of retinal disease characterized by the selective death of retinal ganglion cells (RGCs). However, the pathogenesis of glaucoma has not been fully elucidated. Transient receptor potential vanilloid 4 (TRPV4) is a pressure-sensitive and calcium-permeable cation channel. TRPV4 is widely distributed in the retina and its sustained activation leads to RGC death; indicating that TRPV4 may be a possible target for glaucoma treatment. Here, we investigated the effects of TRPV4 on RGC apoptosis in a rat model of chronic ocular hypertension (COH), then examined the mechanism underlying these effects.

The COH model was established by injection of micro-magnetic beads into the anterior chamber of adult male rats. The expression levels of TRPV4, glial fibrillary acidic protein, and inflammatory factors were assessed by immunohistochemistry and immunoblotting. RGC apoptosis and visual dysfunction were evaluated by TUNEL assay and photopic negative response. Functional expression of TRPV4 was examined by electrophysiology and calcium imaging. Real-time polymerase chain reaction and immunoblotting were employed to investigate the molecular mechanism underlying the effects of TRPV4 on tumor necrosis factor-α (TNF-α) release.

We found that TRPV4 played an essential role in glaucoma, such that high levels of TRPV4 expression were associated with elevated intraocular pressure. Furthermore, TRPV4 activation was involved in glaucoma-induced RGC apoptosis and RGC-related reductions in visual function. Mechanistic investigation demonstrated that TRPV4 activation led to enhanced Müller cell gliosis and TNF-α release via the JAK2/STAT3/NF-kB pathway, while TRPV4 inhibition could reverse these effects. Finally, TRPV4 activation could lead to elevated expression of TNF receptor 1 in RGCs, while inhibition of TNF-α could reduce TRPV4-mediated RGC apoptosis.

TRPV4 activation induces Müller cell gliosis and TNF-α elevation via the JAK2/STAT3/NF-κB pathway, which may exacerbate RGC apoptosis in glaucoma; these results suggest that TRPV4 can serve as a therapeutic target in glaucoma treatment.

The online version contains supplementary material available at 10.1186/s12974-021-02315-8.

• Apoptosis
• Glaucoma
• Retinal Müller cell
• TNF-α
• TRPV4

• TRPV
• confocal microscopy
• immunofluorescence
• mechanosensitive channel
• patch clamping
• potassium channel
• rod
• temperature

• Animals
• Calcium/metabolism
• Calcium/pharmacology
• Membrane Potentials/drug effects
• Membrane Potentials/physiology
• Photoreceptor Cells/physiology
• Retina/drug effects
• Retina/physiology
• Retinal Neurons/drug effects
• Retinal Neurons/physiology
• Vertebrates/physiology
• Vision, Ocular/drug effects
• Vision, Ocular/physiology

• R01 EY019908 NEI NIH HHS
• EY 004446, EY 019908, Vision Core EY 02520 NIH HHS
• R01 EY004446 NEI NIH HHS
• P30 EY002520 NEI NIH HHS

Müller glia are important in retinal health and disease and are a major source of retinal VEGF-A. Of the different VEGF family members, the role of VEGF-A in retinal health and disease has been studied extensively. The potential contribution of other VEGF family members to retinal pathophysiology, however, remains poorly defined. This study aimed to understand the role of VEGF-B in Müller cell pathophysiology.

The expression of different VEGFs and their receptors in human MIO-M1 and mouse QMMuC-1 Müller cell lines and primary murine Müller cells was examined by RT-PCR, ELISA, and Western blot. The effect of recombinant VEGF-B or VEGF-B neutralization on Müller cell viability and survival under normal, hypoxic, and oxidative (4-hydroxynonenal [4-HNE]) conditions was evaluated by Alamar Blue, Yo-Pro uptake, and immunocytochemistry. The expression of glial fibrillary acidic protein, aquaporin-4, inward rectifying K⁺ channel subtype 4.1, glutamine synthetase, and transient receptor potential vanilloid 4 under different treatment conditions was examined by RT-PCR, immunocytochemistry, and Western blot. Transient receptor potential vanilloid 4 channel activity was assessed using a Fura-2–based calcium assay.

VEGF-B was expressed in Müller cells at the highest levels compared with other members of the VEGF family. VEGF-B neutralization did not affect Müller cell viability or functionality under normal conditions, but enhanced hypoxia– or 4-HNE–induced Müller cell death and decreased inward rectifying K⁺ channel subtype 4.1 and aquaporin-4 expression. Recombinant VEGF-B restored Müller cell glutamine synthetase expression under hypoxic conditions and protected Müller cells from 4-HNE–induced damage by normalizing transient receptor potential vanilloid 4 channel expression and activity.

Autocrine production of VEGF-B protects Müller cells under pathologic conditions.

The intraocular pressure inside the human eye maintains 10–21 mmHg above the atmospheric pressure. Elevation of intraocular pressure is highly correlated with the retinopathy in glaucoma, and changes in the exterior pressure during mountain hiking, air traveling, and diving may also induce vision decline and retinopathy. The pathophysiological mechanism of these pressure-induced retinal disorders has not been completely clear. Retinal neurons express pressure-sensitive channels intrinsically sensitive to pressure and membrane stretch, such as the transient receptor potential channel (TRP) family permeable to Ca²⁺ and Na⁺ and the two-pore domain K channel family. Recent data have shown that pressure excites the primate retinal bipolar cell by opening TRP vanilloid 4 to mediate transient depolarizing currents, and TRP vanilloid 4 agonists enhance the membrane excitability of primate retinal ganglion cells. The eyeball wall is constructed primarily by the sclera and cornea of low elasticity, and the flow rate of the aqueous humor and intraocular pressure both fluctuate, but the mathematical relationship between the ocular elasticity, aqueous humor volume, and intraocular pressure has not been established. This review will briefly review recent literature on the pressure-related retinal pathophysiology in glaucoma and other pressure-induced retinal disorders, the elasticity of ocular tissues, and pressure-sensitive cation channels in retinal neurons. Emerging data support the global volume and the elasticity and thickness of the sclera and cornea as variables to affect the intraocular pressure level like the volume of the aqueous humor. Recent results also suggest some potential routes for TRPs to mediate retinal ganglion cell dysfunction: TRP opening upon intraocular pressure elevation and membrane stretch, enhancing glutamate release from bipolar cells, increasing intracellular Na⁺, Ca²⁺ concentration in retinal ganglion cells and extracellular glutamate concentration, inactivating voltage-gated Na⁺ channels, and causing excitotoxicity and dysfunction of retinal ganglion cells. Further studies on these routes likely identify novel targets and therapeutic strategies for the treatment of pressure-induced retinal disorders.

• TRP
• glaucoma
• ocular elasticity
• patch-clamp
• pressure-sensitive ion channel
• retina
• retinal bipolar cell
• retinal ganglion cell

• Angiogenesis
• Calcium channel
• Cornea
• Diabetic retinopathy
• Glaucoma
• Lens
• Osmolarity
• Retina
• TRPV4

• GABAA receptor
• TRPV4
• glycine receptor
• inhibitory input
• retinal ganglion cell

Oxidative stress is implicated in retinal cell injury associated with glaucoma and other retinal diseases. However, the mechanism by which oxidative stress leads to retinal damage is not completely understood. Transient receptor potential ankyrin 1 (TRPA1) is a redox-sensitive channel that, by amplifying the oxidative stress signal, promotes inflammation and tissue injury. Here, we investigated the role of TRPA1 in retinal damage evoked by ischemia (1 hour) and reperfusion (I/R) in mice. In wild-type mice, retinal cell numbers and thickness were reduced at both day-2 and day-7 after I/R. By contrast, mice with genetic deletion of TRPA1 were protected from the damage seen in their wild-type littermates. Daily instillation of eye drops containing two different TRPA1 antagonists, an oxidative stress scavenger, or a NADPH oxidase-1 inhibitor also protected the retinas of C57BL/6J mice exposed to I/R. Mice with genetic deletion of the proinflammatory TRP channels, vanilloid 1 (TRPV1) or vanilloid 4 (TRPV4), were not protected from I/R damage. Surprisingly, genetic deletion or pharmacological blockade of TRPA1 also attenuated the increase in the number of infiltrating macrophages and in the levels of the oxidative stress biomarker, 4-hydroxynonenal, and of the apoptosis biomarker, active caspase-3, evoked by I/R. These findings suggest that TRPA1 mediates the oxidative stress burden and inflammation that result in murine retinal cell death. We also found that TRPA1 (both mRNA and protein) is expressed by human retinal cells. Thus, it is possible that inhibition of a TRPA1-dependent pathway could also attenuate glaucoma-related retinal damage.