Specific inhibition of TRPV4 enhances retinal ganglion cell survival in adult porcine retinal explants.
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.
Department of Ophthalmology, Lund University, SE 22184, Lund, Sweden. Electronic address: linnea.taylor@med.lu.se.
Linnéa
L
Taylor
Department of Ophthalmology, Lund University, SE 22184, Lund, Sweden.
Karin
K
Arnér
Department of Ophthalmology, Lund University, SE 22184, Lund, Sweden.
Fredrik
F
Ghosh
D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046509:Tissue Culture Techniques
C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; C544743:RN 1734; D013449:Sulfonamides; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D007930:Leucine
Ganglion cells; Gliosis; Retina; Retinal degeneration; TRPV4