Potassium channels including ATP-sensitive potassium channel (K_ATP) are important to the physiologic role of H₂S (Zhao et al., 2001; Geng et al., 2004). Given the well-known regulatory effect of potassium channels in the retina (Cordeiro et al., 2011), it is reasonable to hypothesize that H₂S modulates retinal function by acting on the potassium channel. Njie-Mbye et al. found that glibenclamide, a K_ATP channel inhibitor, inhibited the H₂S donor NaHS-induced cyclic adenosine monophosphate (cAMP) formation in rat retinal pigment epithelial (RPE) cells, suggesting that K_ATP-channel might be involved in the effect of H₂S on the cAMP-related RPE cell proliferation, apoptosis, and phagocytosis (Njie-Mbye et al., 2012). NaHS was found to have a prominent relaxation effect on the retina arteries by acting on the voltage-dependent potassium channel (K_v) and inwardly rectifying potassium channel (K_ir) (Takır et al., 2015), indicating that H₂S may play an important role in regulating the retina vascular system.

The calcium transport system exists in retinal Müller cells as well as RPE (Bringmann et al., 2000; Wimmers et al., 2006), and the change in these channels may contribute to the retinal degenerative diseases (Wimmers et al., 2006). Mikami et al. (2011) found that intracellular Ca²⁺ inhibited CAT/3MST-derived H₂S production in retinal lysates and in turn H₂S blocked high K⁺-induced Ca²⁺ influx via activating V-ATPase in the outer nuclear layer (ONL) and outer plexiform layer (OPL). The counteraction between the H₂S and intracellular Ca²⁺ in the retina mediated the protective effect of H₂S on the retinal photoreceptor apoptosis caused by excessive light (Mikami et al., 2011).

Besides K⁺ and Ca²⁺ channels, other ion channels such as sodium and chloride channels are believed to have an important effect on various physiologic processes in the retina (Zhang et al., 2011; Smith et al., 2017). However, whether H₂S acts on the sodium and chloride channels has not been clear yet. Therefore, further studies need to be done to explore the possible relationship between retina-derived H₂S and the ion channels.

Glutamate is an important neurotransmitter and plays a key role in the fast excitatory synaptic transmission in the CNS. Therefore, glutamate has been reported to be implicated in the physiologic processes such as neuronal development and synaptic plasticity and pathophysiologic processes such as excitotoxicity (Seki et al., 2010). [³H]D-aspartate is a substitute for glutamate in neurotransmitter release assay. Opere et al. (2009) found that both NaHS and Na₂S donors inhibited high K⁺-evoked [³H]D-aspartate release from isolated bovine and porcine retinae. Although the mechanisms were unclear, but it is supposed that there might be an involvement of glutamate aspartate transporter which lowers the extracellular glutamate level to protect the neurons against excitotoxic damage. One study suggested that a derivative of latanoprost acid (ACS67), which can release H₂S, had a remarkable effect on increasing glutathione (GSH) and cyclic guanosine monophosphate (cGMP) levels in the aqueous humor (Perrino et al., 2009). In the retina, the glutamate aspartate transporter is located in Müller cells and maintains the level of GSH with the toxic effects of glutamate (Martin et al., 2012). Therefore, this transporter might be a target of H₂S to regulate neurotransmission in the retina. Future studies of the exact mechanisms are needed.

Retinal degenerative diseases, commonly including retinitis pigmentosa (RP), age-related macular degeneration (AMD), and glaucomatous retinal neuropathy, share the main pathological basis of abnormal structure and function of retinal neurons at all levels, which results in an irreversible damage to visual acuity (Cottet and Schorderet, 2009).

Progressive degeneration of the photoreceptor cells in the retina contributes to the severe visual injury of RP and AMD (Busskamp et al., 2010). The photoreceptor cell apoptosis is a key pathologic basis of human retinal degeneration and light-induced retinal degeneration models (Wenzel et al., 2005; Rajala and Rajala, 2013). In one study, NaHS administration suppressed the light-induced photoreceptor degeneration in association with decreasing photoreceptor cell apoptosis and DNA damage in the retinal ONL in a mice retinal degeneration model caused by excessive light exposure. Simultaneously, NaHS prevented high K⁺-evoked Ca²⁺ influx in mice retinal ONL and OPL (Mikami et al., 2011), suggesting that restoring Ca²⁺ homeostasis might be involved in the protective effect of H₂S on the photoreceptor cell apoptosis. The above findings indicate that H₂S might act as a neuroprotector to prevent from retinal degeneration. On the other hand, abnormal function of RPE cells is an important pathological process of RP and AMD (Da et al., 2007; Liu et al., 2015). H₂S donor NaHS and endogenous H₂S were found to dose-dependently increase cAMP concentrations in rat RPE cells (Njie-Mbye et al., 2010), while the increase in intracellular cAMP level resulted in the downregulation of phagocytic activity of RPE cells, which would lead to the progression of RP and AMD (Hall et al., 1993; Kuriyama et al., 1995). The above facts suggest that H₂S might aggravate the process of RP and AMD. Collectively, whether H₂S has a protective or deleterious effect on RP and AMD needs further research.

Although glaucoma is not usually described as a retinal disease, glaucomatous retinal neuropathy is the leading cause of vision impairment in glaucoma (Low et al., 2015). Recently, H₂S levels and expression of its endogenous enzymes CBS, CSE, and 3MST in retinal tissues were significantly decreased along with the loss of retinal ganglion cells (RGCs) in a chronic ocular-hypertension rat model. While the treatment with NaHS could improve the survival of RGCs without impacting on the intraocular pressure (Huang et al., 2017). However, Perrino et al. (2009) found that H₂S-releasing agent ACS67 reduced the intraocular pressure in carbomer-induced glaucoma in rabbits and increased the GSH and cGMP content in aqueous humor. The above interesting results give a better understanding of the pathogenesis of glaucomatous retinal neuropathy and provide a potential therapeutic target for glaucoma.

Retinal vascular diseases are defined as diseases first caused by a retinal vascular abnormality, which leads to injured retinal neurons or vision. The diseases mainly include retinal artery occlusion (RAO), retinal vein occlusion (RVO), and diabetic retinopathy (DR).

In retinal vascular occlusion, including RAO and RVO, ischemia/reperfusion (I/R) injury plays a significant role in the pathologic process (Archer, 1976). It causes RGCs death by inducing apoptosis and necrosis (Hayreh et al., 2004). Intravitreal injection of the H₂S donor ACS67 could prevent the retinal injury caused by elevated intraocular pressure-induced retina I/R in an in vivo experiment. Furthermore, in vitro study showed that ACS67 suppressed H₂O₂-induced RGC-5 cell apoptosis and improved RGC-5 cell viability via increasing the GSH level and decreasing reactive oxygen species level (Osborne et al., 2010). Biermann et al. (2011) found that inhaled H₂S preconditioning attenuated RGC death after retina I/R injury. NF-κB, ERK/MAPK, and JNK/MAPK pathways were involved in the anti-apoptotic mechanisms for H₂S preconditioning (Biermann et al., 2011). Additionally, H₂S could relax retinal arteries by targeting on the potassium channel (Takır et al., 2015), which might be involved in the protective effect of H₂S on the retinal vascular diseases.

DR, due to diabetes, is a globally increasingly important retinal disease (Whiting et al., 2011). High glucose-induced retinal microvasculopathy is one of the important causes of reduced visual acuity and acquired blindness. The injured pericytes and capillary blockage due to a high glucose environment, which further leads to generation of vascular endothelial growth factor (VEGF), are the most critically early pathological changes during DR (Lu and Adamis, 2002). The process further leads to the breakdown of the blood–retinal barrier, leakage of retinal capillaries, macular edema, and neovascularization. In streptozotocin-induced diabetic rats, retina H₂S level and CSE and 3MST mRNA were decreased. The treatment of NaHS could reduce blood–retinal barrier permeability and acellular capillaries formation in the retina along with the reduced vitreous content of VEGF and its signaling pathway (Si et al., 2013), suggesting that retina-derived H₂S might protect against high glucose-induced retinal microvasculopathy. However, in another study, H₂S was found to play different roles in the development of retinal neovascularization in diabetic patients with proliferative DR (PDR). Ran et al. (2014) revealed that H₂S level was increased in both the plasma and the vitreous body of diabetic patients with PDR when compared with that in healthy people and diabetic patients without PDR. In accordance with the increase in H₂S level, VEGF levels in the vitreous body from diabetic patients with PDR were also significantly elevated. The above clinical data suggest that H₂S might act as a pro-angiogenesis factor to promote the progression of PDR (Ran et al., 2014), which is similar to the role of H₂S in the development of angiogenesis in cardiovascular diseases (Cai et al., 2007; Papapetropoulos et al., 2009; Wang et al., 2010). Recently, retina neurodegeneration was found to occur ahead of vascular injury during DR (Aizu et al., 2003; Ozkaya et al., 2017). Si et al. (2013) found that NaHS improved retinal neuronal dysfunction in streptozotocin-treated rats representing the facts that NaHS enhanced b-wave amplitudes and oscillatory potentials. The underlying mechanisms responsible for the neuroprotective effect of H₂S in retina included suppressing oxidative stress, protecting mitochondrial function, and inhibiting inflammation. Taken together, H₂S plays a complex role in the pathogenesis of DR. Further studies are needed to discover the effect and mechanisms for H₂S in DR, which might hopefully deepen the understanding of the DR pathophysiology and help to find new treatments for this disease.