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 (TRPV...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Qian Li, Yun Cheng, Shenghai Zhang, Xinghuai Sun, Jihong Wu
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	TRPV4 Retinal Müller cell TNF-α Apoptosis Glaucoma Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/eabee6112d404a33a7af2bfc50f692b5
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:eabee6112d404a33a7af2bfc50f692b5
record_format	dspace
spelling	oai:doaj.org-article:eabee6112d404a33a7af2bfc50f692b52021-11-21T12:39:54ZTRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway10.1186/s12974-021-02315-81742-2094https://doaj.org/article/eabee6112d404a33a7af2bfc50f692b52021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02315-8https://doaj.org/toc/1742-2094Abstract 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.Qian LiYun ChengShenghai ZhangXinghuai SunJihong WuBMCarticleTRPV4Retinal Müller cellTNF-αApoptosisGlaucomaNeurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-22 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TRPV4 Retinal Müller cell TNF-α Apoptosis Glaucoma Neurology. Diseases of the nervous system RC346-429
spellingShingle	TRPV4 Retinal Müller cell TNF-α Apoptosis Glaucoma Neurology. Diseases of the nervous system RC346-429 Qian Li Yun Cheng Shenghai Zhang Xinghuai Sun Jihong Wu TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway
description	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.
format	article
author	Qian Li Yun Cheng Shenghai Zhang Xinghuai Sun Jihong Wu
author_facet	Qian Li Yun Cheng Shenghai Zhang Xinghuai Sun Jihong Wu
author_sort	Qian Li
title	TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway
title_short	TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway
title_full	TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway
title_fullStr	TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway
title_full_unstemmed	TRPV4-induced Müller cell gliosis and TNF-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via JAK2/STAT3/NF-κB pathway
title_sort	trpv4-induced müller cell gliosis and tnf-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via jak2/stat3/nf-κb pathway
publisher	BMC
publishDate	2021
url	https://doaj.org/article/eabee6112d404a33a7af2bfc50f692b5
work_keys_str_mv	AT qianli trpv4inducedmullercellgliosisandtnfaelevationmediatedretinalganglioncellapoptosisinglaucomatousratsviajak2stat3nfkbpathway AT yuncheng trpv4inducedmullercellgliosisandtnfaelevationmediatedretinalganglioncellapoptosisinglaucomatousratsviajak2stat3nfkbpathway AT shenghaizhang trpv4inducedmullercellgliosisandtnfaelevationmediatedretinalganglioncellapoptosisinglaucomatousratsviajak2stat3nfkbpathway AT xinghuaisun trpv4inducedmullercellgliosisandtnfaelevationmediatedretinalganglioncellapoptosisinglaucomatousratsviajak2stat3nfkbpathway AT jihongwu trpv4inducedmullercellgliosisandtnfaelevationmediatedretinalganglioncellapoptosisinglaucomatousratsviajak2stat3nfkbpathway
_version_	1718418920083292160

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

Ejemplares similares