TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

“…For instance, VEGF release, particularly the isoform VEGFA [ 179 , 180 ], in combination with reactive oxygen species (ROS) production in diabetic retinopathy has been shown to enhance retinal degeneration [ 181 ], whereas VEGFD is protective for RGCs and the retinal vasculature [ 182 ]. In addition, the secretion of TNF-α has been shown to exert early neuroprotective effects [ 183 ] but to ultimately induce Müller cell gliosis and RGC death in the glaucomatous retina [ 184 ]. Upon a neuroinflammatory insult, the quiescent and neuroprotective Müller glia undergo reactive, proliferating gliosis [ 185 ], which in turn enhances pathological angiogenesis [ 186 , 187 ] and increases RGC vulnerability to retinal injury [ 169 ].…”

YTHDF1 Negatively Regulates Treponema pallidum-Induced Inflammation in THP-1 Macrophages by Promoting SOCS3 Translation in an m6A-Dependent Manner

“…Mechanistically, we propose that METTL3 promotes the m6A methylation of SOCS3 mRNA, and then YTHDF1 recognizes and binds to the m6A-containing mRNA of SOCS3 and promotes SOCS3 protein expression. Previous studies have demonstrated that the JAK2–STAT3 pathway is involved in the expression and secretion of the inflammatory cytokines TNF-α and IL-1β ( 33 , 34 ). Our results further suggest that YTHDF1 and SOCS3 negatively regulate the inflammatory response by regulating the JAK2–STAT3 pathway.…”

Involvement of transient receptor potential channels in ocular diseases: a narrative review

“…Another channel through which ganglion cell apoptosis may be mediated is TRPV4. Immunochemistry has shown that a substantial amount of TRPV4 is localized in RGCs and the plexiform layers in the rat and porcine retinas (150,151). In many species, TRPV4 has been observed in RGC dendrites, somas and axon bundles in the retina, the optic nerve head, and the laminar region of the optic nerve (121,150,(152)(153)(154).…”

“…Inhibition of TRPV4 channels within the retina has been reported to improve the survival of RGCs ( 150 ). Also, intraocular injection of TRPV4 antagonists has been found to lower IOP in glaucomatous mouse eyes and to protect retinal neurons from IOP-induced cell death by mediating the JAK2/STAT3/NF-κB signaling pathway ( 151 ). These findings indicate that inhibition of TRPV4 could be used as a potential treatment for glaucoma.…”