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

Published on Jan 1, 2017in Experimental Eye Research3.011
· DOI :10.1016/J.EXER.2016.11.002
Linnéa Taylor9
Estimated H-index: 9
(Lund University),
Karin Arnér17
Estimated H-index: 17
(Lund University),
Fredrik Ghosh19
Estimated H-index: 19
(Lund University)
Sources
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 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 Muller 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.
📖 Papers frequently viewed together
606 Citations
141 Citations
3 Citations
References32
Newest
#1Linnéa Taylor (Lund University)H-Index: 9
#2Karin Arnér (Lund University)H-Index: 17
Last. Fredrik Ghosh (Lund University)H-Index: 19
view all 3 authors...
N-methyl-N-nitrosourea (MNU) has been reported to induce photoreceptor-specific degeneration with minimal inner retinal impact in small animals in vivo. Pending its use within a retinal transplantation paradigm, we here explore the effects of MNU on outer and inner retinal neurons and glia in an in vitro large animal model of retinal degeneration. The previously described degenerative culture explant model of adult porcine retina was used and compared with explants receiving 10 or 100 μg/ml MNU ...
17 CitationsSource
#1Fredrik Ghosh (Lund University)H-Index: 19
#2Karin Arnér (Lund University)H-Index: 17
Last. Linnéa Taylor (Lund University)H-Index: 9
view all 3 authors...
Background To illustrate the importance of biomechanical impact on tissue health within the central nervous system (CNS), we herein describe an in vitro model of rhegmatogenous retinal detachment (RRD) in which disruption and restoration of physical tissue support can be studied in isolation.
5 CitationsSource
#1Oscar Manouchehrian (Lund University)H-Index: 4
#2Karin Arnér (Lund University)H-Index: 17
Last. Linnéa Taylor (Lund University)H-Index: 9
view all 4 authors...
Background Retinal ischemia results in a progressive degeneration of neurons and a pathological activation of glial cells, resulting in vision loss. In the brain, progressive damage after ischemic insult has been correlated to neuroinflammatory processes involving microglia. Galectin-3 has been shown to mediate microglial responses to ischemic injury in the brain. Therefore, we wanted to explore the contribution of Galectin-3 (Gal-3) to hypoperfusion-induced retinal degeneration in mice.
19 CitationsSource
#1Daniel A. Ryskamp (UofU: University of Utah)H-Index: 15
#2Anthony Iuso (UofU: University of Utah)H-Index: 7
Last. David Križaj (UofU: University of Utah)H-Index: 21
view all 3 authors...
A perennial challenge in neuroscience research has been to elucidate the role of astrocytes, the most numerous cell type in the CNS, at all levels of brain function from development and cognition to trauma and death of the organism. The many types of astrocyte tend to have in common the regulation of water/ion transport, metabolic homeostasis and inflammatory signaling. Prominent expression of volume-sensitive ion channels and aquaporins ensures that even small activity-induced changes in extrac...
18 CitationsSource
#1Daniel A. RyskampH-Index: 15
#2Andrew O. JoH-Index: 7
Last. David KrižajH-Index: 21
view all 7 authors...
Activity-dependent shifts in ionic concentrations and water that accompany neuronal and glial activity can generate osmotic forces with biological consequences for brain physiology. Active regulation of osmotic gradients and cellular volume requires volume-sensitive ion channels. In the vertebrate retina, critical support to volume regulation is provided by Muller astroglia, but the identity of their osmosensor is unknown. Here, we identify TRPV4 channels as transducers of mouse Muller cell volu...
60 CitationsSource
#1Nobuaki Takahashi (Kyoto University)H-Index: 25
#2Sayaka Hamada-Nakahara (UTokyo: University of Tokyo)H-Index: 3
Last. Shiro Suetsugu (UTokyo: University of Tokyo)H-Index: 51
view all 16 authors...
Mutations in the ankyrin repeat domain (ARD) of TRPV4 are responsible for several channelopathies but little is known about the physiological function of this domain. Here the authors show that phosphoinositide binding to TRPV4 ARD leads to suppression of the channel activity, and obtain the crystal structure of the domain in complex with inositol-1,4,5-trisphosphate.
57 CitationsSource
#1Jae Chul Lee (New Generation University College)H-Index: 4
#1Jae Chul Lee (SNU: Seoul National University)H-Index: 8
Last. Soo Young Choe (CBNU: Chungbuk National University)H-Index: 12
view all 2 authors...
Transient receptor potential vanilloid type 4 (TRPV4) channels are expressed in the central nervous system, but their role in regulating the aging process under physiological and pathological conditions is still largely unknown. To identify age-related changes in the TRPV4 channel that contribute to the central nervous system, we investigated the distribution of TRPV4 in the brain and spinal cord regions of adult and aged rats. The expression of TRPV4 in the brain and spinal cord of adult and ag...
29 CitationsSource
Purpose: The purpose of this study was to explore the importance of local physical tissue support for homeostasis in the isolated retina. Methods: Full-thickness retinal sheets were isolated from adult porcine eyes. Retinas were cultured for 5 or 10 days using the previously established explant protocol with photoreceptors positioned against the culture membrane (porous polycarbonate) or the Muller cell endfeet and inner limiting membrane (ILM) apposed against the membrane. The explants were ana...
17 CitationsSource
#1David Križaj (Visual Sciences)H-Index: 2
#1David Križaj (Visual Sciences)H-Index: 21
Last. Valery I. Shestopalov (UM: University of Miami)H-Index: 30
view all 7 authors...
Purpose of the study: Many blinding diseases of the inner retina are associated with degeneration and loss of retinal ganglion cells (RGCs). Recent evidence implicates several new signaling mechanisms as causal agents associated with RGC injury and remodeling of the optic nerve head. Ion channels such as Transient receptor potential vanilloid isoform 4 (TRPV4), pannexin-1 (Panx1) and P2X7 receptor are localized to RGCs and act as potential sensors and effectors of mechanical strain, ischemia and...
100 CitationsSource
#1Ming Shi (Fourth Military Medical University)H-Index: 22
#2Fang Du (Fourth Military Medical University)H-Index: 7
Last. Gang Zhao (Fourth Military Medical University)H-Index: 28
view all 12 authors...
Vibroacoustic disease, a progressive and systemic disease, mainly involving the central nervous system, is caused by excessive exposure to low-frequency but high-intensity noise generated by various heavy transportations and machineries. Infrasound is a type of low-frequency noise. Our previous studies demonstrated that infrasound at a certain intensity caused neuronal injury in rats but the underlying mechanism(s) is still largely unknown. Here, we showed that glial cell-expressed TRPV4, a Ca2+...
43 CitationsSource
Cited By15
Newest
#1Ji-Jie Pang (BCM: Baylor College of Medicine)H-Index: 15
#2Fan Gao (BCM: Baylor College of Medicine)H-Index: 13
Last. Samuel M. Wu (BCM: Baylor College of Medicine)H-Index: 48
view all 3 authors...
(1) Background: High-tension glaucoma damages the peripheral vision dominated by rods. How mechanosensitive channels (MSCs) in the outer retina mediate pressure responses is unclear. (2) Methods: Immunocytochemistry, patch clamp, and channel fluorescence were used to study MSCs in salamander photoreceptors. (3) Results: Immunoreactivity of transient receptor potential channel vanilloid 4 (TRPV4) was revealed in the outer plexiform layer, K+ channel TRAAK in the photoreceptor outer segment (OS), ...
Source
#1Hussain Rao (UMKC: University of Missouri–Kansas City)
Last. Peter KoulenH-Index: 22
view all 4 authors...
Diabetic retinopathy (DR) is a significant cause of vision loss and a research subject that is constantly being explored for new mechanisms of damage and potential therapeutic options. There are many mechanisms and pathways that provide numerous options for therapeutic interventions to halt disease progression. The purpose of the present literature review is to explore both basic science research and clinical research for proposed mechanisms of damage in diabetic retinopathy to understand the ro...
Source
#1Sarah RedmonH-Index: 6
#1Sarah N. Redmon (Visual Sciences)
Last. David KrižajH-Index: 21
view all 7 authors...
The physiological and neurological correlates of plummeting brain osmolality during edema, traumatic CNS injury, and severe ischemia are compounded by neuroinflammation. Using multiple approaches, we investigated how retinal microglia respond to challenges mediated by increases in strain, osmotic gradients, and agonists of the stretch-activated cation channel TRPV4. Dissociated and intact microglia were TRPV4-immunoreactive and responded to the selective agonist GSK1016790A and substrate stretch...
2 CitationsSource
#1Ivan Fernandez-Bueno (University of Valladolid)H-Index: 12
#2Ricardo Usategui-Martín (University of Valladolid)H-Index: 9
Ex vivo neuroretina cultures closely resemble in vivo conditions, retaining the complex neuroretina cells dynamics, connections, and functionality, under controlled conditions. Therefore, these models have allowed advancing in the knowledge of retinal physiology and pathobiology over the years. Furthermore, the ex vivo neuroretina models represent an adequate tool for evaluating stem cell therapies over neuroretinal degeneration processes.Here, we describe a physically separated co-culture of ne...
Source
#1Brianna D. Guarino (NEOMED: Northeast Ohio Medical University)H-Index: 2
#2Sailaja Paruchuri (University of Akron)H-Index: 24
Last. Charles K. Thodeti (NEOMED: Northeast Ohio Medical University)H-Index: 26
view all 3 authors...
Transient potential receptor vanilloid 4 (TRPV4) is an ion channel responsible for sensing osmotic and mechanical signals, which in turn regulates calcium signaling across cell membranes. TRPV4 is widely expressed throughout the body, and plays an important role in normal physiological function, as well as different pathologies, however, its role in the eye is not well known. In the eye, TRPV4 is expressed in various tissues, such as the retina, corneal epithelium, ciliary body, and the lens. In...
3 CitationsSource
#1Qian LiH-Index: 78
Last. Jihong WuH-Index: 21
view all 5 authors...
The transient receptor potential vanilloid 4 (TRPV4) channel is widely distributed in the retina. Activation of the TRPV4 channel enhances excitatory signaling from bipolar cells to retinal ganglion cells (RGCs), thereby increasing RGC firing rate and membrane excitability. In this study, we investigated the effect of TRPV4 channel activation on the miniature inhibitory postsynaptic current (mIPSC) in rat RGCs. Our results showed that perfusion with HC-067047, a TRPV4-channel antagonist, signifi...
Source
#1Maria Luz Alonso-Alonso (University of Valladolid)H-Index: 6
#2Girish K. Srivastava (University of Valladolid)H-Index: 14
Last. Ivan Fernandez-Bueno (University of Valladolid)H-Index: 12
view all 6 authors...
Mesenchymal stem cells (MSC) secrete neuroprotective molecules that may be useful as an alternative to cell transplantation itself. Our purpose was to develop different pharmaceutical compositions based on conditioned medium (CM) of adipose MSC (aMSC) stimulated by and/or combined with nicotinamide (NIC), vasoactive intestinal peptide (VIP), or both factors; and to evaluate in vitro their proliferative and neuroprotective potential. Nine pharmaceutical compositions were developed from 3 experime...
1 CitationsSource
#1Sonia Labrador-Velandia (University of Valladolid)H-Index: 2
#2Maria Luz Alonso-Alonso (University of Valladolid)H-Index: 6
Last. Ivan Fernandez-Bueno (University of Valladolid)H-Index: 12
view all 7 authors...
Abstract Through the paracrine effects of stem cells, including the secretion of neurotrophic, immunomodulatory, and anti-apoptotic factors, cell-based therapies offer a new all-encompassing approach to treatment of neurodegenerative diseases. In this study, we used physically separated co-cultures of porcine neuroretina (NR) and human mesenchymal stem cells (MSC) to evaluate the MSC paracrine neuroprotective effects on NR degeneration. NR explants were obtained from porcine eyes and cultured al...
12 CitationsSource
#1Fan Gao (BCM: Baylor College of Medicine)H-Index: 13
#2Zhuo Yang (BCM: Baylor College of Medicine)H-Index: 8
Last. Ji-Jie Pang (BCM: Baylor College of Medicine)H-Index: 15
view all 5 authors...
The transient receptor potential vanilloid 4 (TRPV4) channel may be opened by mechanical stimuli to mediate Ca2+ and Na+ influxes, and it has been suggested to mediate glaucoma retinopathy. However, it has been mostly unclear how TRPV4 activities affect the function of primate retinal ganglion cells (RGCs). We studied RGCs and bipolar cells (BCs) in the peripheral retina of the old-world primate using whole-cell current-clamp and voltage-clamp recordings, immunomarkers and confocal microscopy. R...
6 CitationsSource
#1Aparna Murali (UQ: University of Queensland)H-Index: 2
#2Charmaine A. Ramlogan-Steel (Central Queensland University)H-Index: 6
Last. Christopher J. Layton (UQ: University of Queensland)H-Index: 11
view all 5 authors...
The retina is the tissue responsible for light detection, in which retinal neurons convert light energy into electrical signals to be transported towards the visual cortex. Damage of retinal neurons leads to neuronal cell death and retinal pathologies, compromising visual acuity and eventually leading to irreversible blindness. Models of retinal neurodegeneration include 2D systems like cell lines, disassociated cultures and co-cultures, and 3D models like organoids, organotypic retinal cultures...
18 CitationsSource