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Modulation of TRPV4-mediated TNF-α expression in Müller glia and subsequent RGC apoptosis by statins
Go Woon Choi1, Mi-Lyang Kim1, Kyung Rim Sung2
1Biomedical Research Center, Asan Medical Center, College of Medicine, University of Ulsan, 88, Olympic-Ro 43-Gil, Songpa-gu, Seoul, 05505, South Korea.
Abstract:
In addition to regulating cholesterol synthesis, statins have neuroprotective effects. Apoptosis of retinal ganglion cells (RGCs) causes a gradual loss of visual function in glaucoma. This study aimed to investigate the neuroprotective effect of statins on the RGC apoptosis induced by activated Müller glia. Primary Müller cells and RGCs were cultured from the retina of C57BL6 mice. Müller cells were activated with GSK101, a transient receptor potential vanilloid 4 (TRPV4) agonist, and tumor necrosis factor-alpha (TNF-α) released to the medium was measured using an enzyme-linked immunosorbent assay. Cells were pretreated with simvastatin or lovastatin before GSK101. RGCs were treated with conditioned media from Müller glia cultures, and apoptosis was determined using flow cytometry. TRPV4 activation through GSK101 treatment induced gliosis of Müller cells, and the conditioned media from activated Müller cells was potent to induce RGC apoptosis. Statins suppress both gliosis in Müller cells and subsequent RGC apoptosis. TNF-α release to the media was increased in GSK101-treated Müller cells, and TNF-α in the conditioned media was the critical factor causing RGC apoptosis. The increase in TRPV4-mediated TNF-α expression occurred through the nuclear factor kappa-light chain enhancer of activated B cell pathway activation, which was inhibited by statins. Herein, we showed that statins can modulate gliosis and TNF-α expression in Müller cells, protecting RGCs. These data further support the neuroprotective effect of statins, promoting them as a potential treatment for glaucoma.
Insights
Statins protect retinal ganglion cells (RGCs) from apoptosis by inhibiting Müller glial activation and tumor necrosis factor-alpha (TNF-α) release. These findings suggest statins as a potential glaucoma treatment.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- Glaucoma is characterized by retinal ganglion cell (RGC) apoptosis, leading to vision loss.
- Statins, known for cholesterol regulation, also exhibit neuroprotective properties.
- Activated Müller glia contribute to RGC apoptosis in glaucoma.
Purpose of the Study:
- To investigate the neuroprotective effects of statins against RGC apoptosis induced by activated Müller glia.
- To elucidate the role of transient receptor potential vanilloid 4 (TRPV4) and tumor necrosis factor-alpha (TNF-α) in this process.
Main Methods:
- Primary Müller cells and RGCs were cultured from C57BL6 mice.
- Müller cells were activated using GSK101 (TRPV4 agonist), and TNF-α release was measured.
- Cells were pretreated with simvastatin or lovastatin before activation.
- RGC apoptosis was assessed after treatment with conditioned media from activated Müller cells.
Main Results:
- GSK101-induced Müller cell activation led to gliosis and increased TNF-α release.
- Conditioned media from activated Müller cells induced RGC apoptosis.
- Statins (simvastatin, lovastatin) inhibited Müller cell gliosis and RGC apoptosis.
- Statins suppressed TRPV4-mediated TNF-α release via the nuclear factor kappa-light chain enhancer of activated B cell pathway.
Conclusions:
- Statins modulate Müller cell gliosis and TNF-α expression, thereby protecting RGCs.
- These findings highlight the potential of statins as a therapeutic strategy for glaucoma.
