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Specific inhibition of TRPV4 enhances retinal ganglion cell survival in adult porcine retinal explants

Taylor, Linnéa LU ; Arnér, Karin LU and Ghosh, Fredrik LU (2017) In Experimental Eye Research 154. p.10-21
Abstract

Signaling through the polymodal cation channel Transient Receptor Potential Vanilloid 4 (TRPV4) has been implicated in retinal neuronal degeneration. To further outline the involvement of this channel in this process, we here explore modulation of Transient Receptor Potential Vanilloid 4 (TRPV4) activity on neuronal health and glial activation in an in vitro model of retinal degeneration. For this purpose, adult porcine retinal explants were cultured using a previously established standard protocol for up to 5 days with specific TRPV4 agonist GSK1016790A (GSK), or specific antagonist RN-1734, or culture medium only. Glial and neuronal cell health were evaluated by a battery of immunohistochemical markers, as well as morphological... (More)

Signaling through the polymodal cation channel Transient Receptor Potential Vanilloid 4 (TRPV4) has been implicated in retinal neuronal degeneration. To further outline the involvement of this channel in this process, we here explore modulation of Transient Receptor Potential Vanilloid 4 (TRPV4) activity on neuronal health and glial activation in an in vitro model of retinal degeneration. For this purpose, adult porcine retinal explants were cultured using a previously established standard protocol for up to 5 days with specific TRPV4 agonist GSK1016790A (GSK), or specific antagonist RN-1734, or culture medium only. Glial and neuronal cell health were evaluated by a battery of immunohistochemical markers, as well as morphological staining. Specific inhibition of TRPV4 by RN-1734 significantly enhanced ganglion cell survival, improved the maintenance of the retinal laminar architecture, reduced apoptotic cell death and attenuated the gliotic response as well as preserved the expression of TRPV4 in the plexiform layers and ganglion cells. In contrast, culture controls, as well as specimens treated with GSK, displayed rapid remodeling and neurodegeneration as well as a downregulation of TRPV4 and the Müller cell homeostatic mediator glutamine synthetase. Our results indicate that TRPV4 signaling is an important contributor to the retinal degeneration in this model, affecting neuronal cell health and glial homeostasis. The finding that pharmacological inhibition of the receptor significantly attenuates neuronal degeneration and gliosis in vitro, suggests that TRPV4 signaling may be an interesting pharmaceutical target to explore for treatment of retinal degenerative disease.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Ganglion cells, Gliosis, Retina, Retinal degeneration, TRPV4
in
Experimental Eye Research
volume
154
pages
10 - 21
publisher
Elsevier
external identifiers
  • scopus:84994592863
  • wos:000397548100002
ISSN
0014-4835
DOI
10.1016/j.exer.2016.11.002
language
English
LU publication?
yes
id
47c746fc-dc06-4954-891f-eff9fe652e53
date added to LUP
2016-12-05 09:19:58
date last changed
2018-01-07 11:38:40
@article{47c746fc-dc06-4954-891f-eff9fe652e53,
  abstract     = {<p>Signaling through the polymodal cation channel Transient Receptor Potential Vanilloid 4 (TRPV4) has been implicated in retinal neuronal degeneration. To further outline the involvement of this channel in this process, we here explore modulation of Transient Receptor Potential Vanilloid 4 (TRPV4) activity on neuronal health and glial activation in an in vitro model of retinal degeneration. For this purpose, adult porcine retinal explants were cultured using a previously established standard protocol for up to 5 days with specific TRPV4 agonist GSK1016790A (GSK), or specific antagonist RN-1734, or culture medium only. Glial and neuronal cell health were evaluated by a battery of immunohistochemical markers, as well as morphological staining. Specific inhibition of TRPV4 by RN-1734 significantly enhanced ganglion cell survival, improved the maintenance of the retinal laminar architecture, reduced apoptotic cell death and attenuated the gliotic response as well as preserved the expression of TRPV4 in the plexiform layers and ganglion cells. In contrast, culture controls, as well as specimens treated with GSK, displayed rapid remodeling and neurodegeneration as well as a downregulation of TRPV4 and the Müller cell homeostatic mediator glutamine synthetase. Our results indicate that TRPV4 signaling is an important contributor to the retinal degeneration in this model, affecting neuronal cell health and glial homeostasis. The finding that pharmacological inhibition of the receptor significantly attenuates neuronal degeneration and gliosis in vitro, suggests that TRPV4 signaling may be an interesting pharmaceutical target to explore for treatment of retinal degenerative disease.</p>},
  author       = {Taylor, Linnéa and Arnér, Karin and Ghosh, Fredrik},
  issn         = {0014-4835},
  keyword      = {Ganglion cells,Gliosis,Retina,Retinal degeneration,TRPV4},
  language     = {eng},
  month        = {01},
  pages        = {10--21},
  publisher    = {Elsevier},
  series       = {Experimental Eye Research},
  title        = {Specific inhibition of TRPV4 enhances retinal ganglion cell survival in adult porcine retinal explants},
  url          = {http://dx.doi.org/10.1016/j.exer.2016.11.002},
  volume       = {154},
  year         = {2017},
}