Glaucoma is a one of the leading causes of irreversible vision loss and is characterised by progressive degeneration of the retinal ganglion cells (RGCs) and associated optic neuropathy [140]. RXR // isotypes are well expressed in adult ocular tissues including retina, and these receptors also play a critical role in post-natal eye development [141]. Our studies have demonstrated that pharmacological activation of RXR performs a neuroprotective role by rescuing RGCs in murine models of glaucoma [9]. Glaucomatous injury reduced the expression of retinal RXR in both microbead-induced increased intraocular pressure (IOP) model and intravitreal glutamate injection-induced excitotoxicity model [9]. The decrease in RXR expression was particularly evident in the inner retinal layers demonstrated using immunohistochemical analysis, where the decline in all the three RXR isotypes was observed [9]. RXR expression was reinstated by treatment with 100 mg/kg of bexarotene that elicited neuroprotective response in both high IOP and excitotoxicity-induced RGC injury conditions [9]. Bexarotene treatment was also shown to impart protection against ER stress in the retina as evident by the suppression of GADD153 and p-PERK, which are increased in the inner retina in glaucoma [9]. This decrease in ER stress response was concomitant with reduced apoptotic pathway activation in the retina. These findings illustrated that pharmacological activation for RXRs is neuroprotective in the neural retina and prevents functional and structural damage induced by glaucoma injury [9]. Furthermore, HDAC is a constituent of large RXR complex with nuclear receptor corepressor (N-CoR), and studies have indicated that HDAC activity is inversely related to RXR activation caused by bexarotene treatment, in glaucoma models [9]. Proteomics analysis of the retinal and vitreous tissues from the post-mortem eyes from open angle glaucoma and aged-matched control eyes showed enrichment of LXR/RXR and FXR/RXR pathways [142, 143]. LXR, RXR, and FXR are important mediators of the lipid signalling including cholesterol metabolism and inflammation indicating the involvement of these biochemical processes in glaucomatous conditions [144]. The enriched LXR/RXR-mediated network components in mass-spectrometric analysis of glaucoma tissues are suggestive of a potential contribution of RXR in overall pathophysiology of glaucoma.
The RA metabolic enzymes show distinct differential expression pattern during early embryonic development, and interestingly their expression is regulated by the RA signaling. Detailed descriptions of the expression patterns of these genes are beyond the scope of this review. Schematic drawing of expression of rdh10, dhrs3, raldh2, cyp26 a1, rar2, and crabp-II at Xenopus gastrula (stage 11) and neurula (stage 14) stages are illustrated in Figure 3, which shows that the RA signaling itself regulates expression of the enzymes for RA biosynthesis and elicits the complexity of RA acting as a morphogen in early embryonic development. Ectopic cyp26 expression can be induced by atRA treatment [92], while the embryos treated with atRA showed down-regulation of raldh2[38] and rdh10[46]. Dhrs3 can also be induced by atRA treatment (RKT Kam, Y Chen, WY Chan and H Zhao. Dhrs3 attenuates the retinoic acid signaling and is required for early embryonic patterning. Submitted). Thus the RA signaling down-regulates the expression of the enzymes for atRA production, but up-regulates enzymes that can reduce atRA level in embryos. Other components in the RA signaling are also responsive to atRA treatment. For example, crabp-II was found to be an atRA-inducible gene [93], and was found to contain a RARE domain in its promoter region [94]. Similarly, rar2 was found to be inducible by atRA treatment in leukemic cell lines [95], and in rat embryos as well [96]. We summarize the regulation of these genes by RA signaling in Figure 4.
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