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Editors Selection IGR 11-1

Basic science: Axoprotection

Comment by Larry Wheeler on:

12178 Subunits of the epithelial sodium channel family are differentially expressed in the retina of mice with ocular hypertension, Dyka FM; May CA; Enz R, Journal of Neurochemistry, 2005; 94: 120-128

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Dyka et al. (IGR 7-1: 451) have demonstrated that epithelial Na+ channel (ENAC) subunits are expressed in the retinas of DBA2/2J mice that have elevated IOP and ganglion cells loss at age six months. Up-regulation of α -ENAC, believed to be the functional (ion channel) subunit of this epithelial Na⁺ channel, was demonstrated in retinal synaptic and nuclear layers, and retinal pigment epithelium (RPE). The γ -ENAC subunit was also upregulated in RPE of DBA/2J mice, but not in RPE of control animals. Importantly, in other regions of the brain ENAC subunits (α -β -γ ) were not up-regulated. In addition, faint labeling (immunohistochemical) occurred in the inner nuclear and ganglion cell layer. What is the clinical significance of these findings? At this point, the functional role of ENAC in neurons is unclear. The authors speculate that the role of α -ENAC in RPE may be to remove extracellular fluid that accumulates in the subretinal space following elevation of IOP. The relationship between fluid accumulation in the subretinal space and elevation of IOP has not been established. More interesting, but not embellished in this study, was the faint labeling in the retinal ganglion cell layer. Here it is less difficult to imagine a neuro-destructive role for α -ENAC in RGCs. A variety of studies in neuronal tissue including optic nerve have shown that under pathophysiological condition, such as mechanical deformation, hypoxia or ischemia, a destructive rise in intracellular Na⁺ via Na⁺ channels or Na⁺ transporters (Na/H exchange) can occur. This Na⁺ overload results in a destructive Ca²⁺ overload via reversal of the Na⁺/Ca⁺⁺ exchanger. This Ca²⁺ overload then causes cell death by activating a variety of neurodestructive Ca²⁺-sensitive pathways. Thus, it is possible that via upregulatrion of α -ENAC in RGCs (due to sustained elevated IOP) Na⁺ overload takes place leading to RGC death following sustained elevation of IOP. This is an attractive, but of course untested alternative explanation of the data. If true, inhibition of ENAC would be expected to help spare ganglion cells (in DBA/2J mice) from the neurodestructive effects of elevated IOP.

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