Hormone receptors in the retina

Sex hormones and sex hormone receptors are present in the retina from an early stage. Many areas of the brain and retina develop in a sexually dimorphic manner during prenatal, perinatal and postnatal development. Salyer et al. using Long-Evans rats found that prenatally and early postnatally in normal rats males had thicker retinas than females. This increased thickness was reduced using flutamide, an androgen inhibitor, but not significantly so compared to normal males or testosterone-treated males, indicating that the process was not entirely mediated through AR. Females at this life-stage had undetectable testosterone levels, but when these females were treated with testosterone their retinal thickness did not differ significantly from normal or testosterone-treated males. To help rule out the conversion of testosterone to estrogen Salyer et al. using immunocytochemistry found no aromatase present in the neuroretina at this stage of development, but they did find quantities of it in the retinal pigment epithelium (RPE) (Salyer et al. 2001). Interestingly, Kobayashi et al. found evidence of 17|3-hydroxysteroid dehydrogenase type IV in the RPE of chick embryo eye. 173-hydroxysteroid dehydrogenase type IV is an enzyme which converts E2 to less reactive estrone (Kobayashi et al. 1997). It has been proposed its function is to protect the embryonic eye against excessive amounts of E2 (Gupta et al. 2005). Messenger RNAs of AR have been found in adult rat retina and uvea, rabbit retina and choroid and human RPE (Rocha et al. 2000; Wickham et al. 2000). In addition, Rocha et al. found the mRNA for 5a reductase, which translates the enzyme which converts testosterone to the more active DHT in the RPE (Rocha et al. 2000). Prabhu et al. found AR protein in all layers of rat retina except the ganglion and outer nuclear layers (Prabhu et al. 2010). However, in an interesting comparison of transformed rat cell lines from brain capillary endothelial cells and retinal capillary endothelial cells, Ohtsuki et al. found dominant expression of AR in the brain capillary cells, but not the retinal capillary cells. DHT acting through AR, in brain capillary endothelial cells (but not the retinal capillary endothelial cells), up-regulated the mRNA for organic anion transporter 3 (OAT3) a protein which is found in blood brain barrier (Ohtsuki et al. 2005).

ERs are nuclear receptors but may be also be located either in the cytoplasm or in the cell plasma membrane (Marquez and Pietras 2001; Simoncini et al. 2000). As discussed, ER has been found in the vascular endothelium of organs other than the gonads including the retina (Gupta et al. 2005; Ogueta et al. 1999; Suzuma et al. 1999). The ligand for either ERa or ERp can be a form of estrogen or a selective estrogen receptor modulator (SERM). ERa has been mapped to the long arm of chromosome 6 and the ERp has been mapped to band q22-24 of chromosome 14 (Enmark and Gustafsson 1999). ERa and ERp are highly conserved with >95% homology for the DNA-binding domain. The two ERs differ functionally in how they are regulated. The P-receptor lacks ligand-independent transcriptional activity as compared to ERa, meaning when the ligand-dependent carboxy area of ERp is blocked from its ligand, it retains very little activity (Manni and Verderame 2002).

The ligand-independent area of ERa usually displays only weak activity; however in certain cell types it can exhibit strong independent activity (Berry et al. 1990). A pre-requisite for transcriptional activity of the estrogen receptors are their compatibilities with certain co-activators (Shibata et al. 1997); thus, differences in the composition of the highly variable (Enmark and Gustafsson 1999) amino area of ERa and ERp results in differences in intrinsic activity related to differences in affinity for their co-activators (Webb et al. 1998). It should also be noted there is significant variability between ERa and ERp in their ligand-binding domains, «50% variability(Enmark and Gustafsson 1999). These differences suggest it may be possible to create pharmaceuticals which could activate one but not the other.

Prior to activation with estrogen, ERa and ERß are held in the nucleus attached to a molecular chaperone such as heat shock protein 90 (HSP90) (Webb et al. 1998). Estrogen combines with estrogen receptors to create either homo- or hetero-dimers (Cowley et al. 1997; Osborne et al. 2000; Pettersson et al. 1997). These dimers combine with appropriate coactivators and bind to estrogen response elements (ERE) on the DNA which consist of an inverted repeat of two halfsites with the consensus motif AGGTCA spaced by 3 base pairs. ERa has been detected in premenopausal human female retinas (descending amounts 35 years>49 years>74 years) and in human male retinas. Interestingly, Ogueta et al. found the amount of ERa in males was intermediate between the levels found in 49 to 74 year old females. They localized ERa in the retina to the nuclei of the outer and inner nuclear layers, the outer plexiform layer (horizontal and bipolar cells), the nuclei of the ganglion cell layer and the RPE (Ogueta et al. 1999). ERß has been localized to the RPE and also to neovascular tissue evolving from the choroid in both males and females in a manner which is dependent on estrogen concentration (Giddabasappa et al. 2010; Gupta et al. 2005; Marin-Castano et al. 2003).

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