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Apical CLC-2 in retinal pigment epithelium is crucial for survival of the outer retina.

ABSTRACT: Knockout of the chloride channel protein 2 (CLC-2; CLCN2) results in fast progressing blindness in mice. Retinal Pigment Epithelium (RPE) and photoreceptors undergo, in parallel, rapid, and profound morphological changes and degeneration. Immunohistochemistry and electron microscopy of the outer retina and electroretinography of the CLC-2 KO mouse demonstrated normal morphology at postnatal day 2, followed by drastic changes in RPE and photoreceptor morphology and loss of vision during the first postnatal month. To investigate whether the RPE or the photoreceptors are the primary cause of the degeneration, we injected lentiviruses carrying HA-tagged CLC-2 with an RPE-specific promotor in the subretinal space of CLC-2-KO mice at the time of eye opening. As expected, CLC-2-HA was expressed exclusively in RPE; strikingly, this procedure rescued the degeneration of both RPE and photoreceptors. Light response in transduced eyes was also recovered. Only a fraction of RPE was transduced with the lentivirus; however, the entire RPE monolayer appears healthy, even the RPE cells not expressing the CLC-2-HA. Surprisingly, in contrast with previous physiological observations that postulate that CLC-2 has a basolateral localization in RPE, our immunofluorescence experiments demonstrated CLC-2 has an apical distribution, facing the subretinal space and the photoreceptor outer segments. Our findings suggest that CLC-2 does not play the postulated role in fluid transport at the basolateral membrane. Rather, they suggest that CLC-2 performs a critical homeostatic role in the subretinal compartment involving a chloride regulatory mechanism that is critical for the survival of both RPE and photoreceptors.

SUBMITTER: Hanke-Gogokhia C

PROVIDER: S-EPMC8252757 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Common clinical features of unilateral retinal pigment epithelium dysgenesis and combined hamartoma of the retina and retinal pigment epithelium.

Project description:BackgroundHerein, we report two cases of unilateral retinal pigment epithelium dysgenesis (URPED) in Chinese patients and explore the relationship between URPED and combined hamartoma of the retina and retinal pigment epithelium (CHRRPE).Case presentationThe lesion margins in the two cases showed pathognomonic clinical features of URPED, namely, a scalloped reticular margin in hyperplastic retinal pigment epithelium and mild fibrosis. The hypoautofluorescence observed by fundus autofluorescence was inverted compared with that observed by fundus fluorescence angiography. A large amount of fibroglial proliferation and disorganization of the retina involving the whole layer, which are also found in peripapillary CHRRPE, were found in the lesions.ConclusionsURPED appears to share some clinical features with CHRRPE, and the relationship between URPED and CHRRPE needs further study.

| S-EPMC8760665 | biostudies-literature

Congenital focal abnormalities of the retina and retinal pigment epithelium.

Project description:This paper reviews the published literature on a group of developmental disorders of the retina and retinal pigment epithelium which result in focal abnormalities in one or both eyes. They are often asymptomatic, found on routine examination and are generally non-progressive. Some are associated with other systemic abnormalities.

| S-EPMC7784997 | biostudies-literature

Degradation of Photoreceptor Outer Segments by the Retinal Pigment Epithelium Requires Pigment Epithelium-Derived Factor Receptor (PEDF-R).

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Phagocytosed photoreceptor outer segments activate mTORC1 in the retinal pigment epithelium.

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OUTER RETINAL TUBULATION IN BIETTI CRYSTALLINE DYSTROPHY ASSOCIATED WITH THE RETINAL PIGMENT EPITHELIUM ATROPHY.

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Ezrin promotes morphogenesis of apical microvilli and basal infoldings in retinal pigment epithelium.

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Project description:A visual pigment-like protein, referred to as peropsin, has been identified by large-scale sequencing of cDNAs derived from human ocular tissues. The corresponding mRNA was found only in the eye, where it is localized to the retinal pigment epithelium (RPE). Peropsin immunoreactivity, visualized by light and electron microscopy, localizes the protein to the apical face of the RPE, and most prominently to the microvilli that surround the photoreceptor outer segments. These observations suggest that peropsin may play a role in RPE physiology either by detecting light directly or by monitoring the concentration of retinoids or other photoreceptor-derived compounds.

| S-EPMC23288 | biostudies-literature

COMBINED AUTOLOGOUS TRANSPLANTATION OF NEUROSENSORY RETINA, RETINAL PIGMENT EPITHELIUM, AND CHOROID FREE GRAFTS.

Project description:PURPOSE:To evaluate the feasibility and initial functional and anatomical outcomes of transplanting a full-thickness free graft of choroid and retinal pigment epithelium (RPE), along with neurosensory retina in advanced fibrosis and atrophy associated with end-stage exudative age-related macular degeneration with and without a concurrent refractory macular hole. METHODS:During vitrectomy, an RPE-choroidal and neurosensory retinal free graft was harvested in nine eyes of nine patients. The RPE-choroidal and neurosensory retinal free graft was either placed subretinally (n = 5), intraretinally to cover the foveal area inside an iatrogenically induced macular hole over the RPE-choroidal graft (n = 3) or preretinally (n = 1) without a retinotomy wherein both free grafts were placed over the concurrent macular hole. Silicone oil endotamponade was used in all cases. RESULTS:Mean follow-up was 7 ± 5.5 months (range 3-19). The mean preoperative visual acuity was ?count fingers (logarithm of the minimum angle of resolution = 2.11, range 2-3), which improved to ?20/800 (logarithm of the minimum angle of resolution 1.62 ± 0.48, range 0.7-2, P = 0.04). Vision was stable in 5 eyes (55.6%) and improved in 4 eyes (44.4%). Reading ability improved in 5 eyes (55.6%). Postoperative complications were graft atrophy (n = 1), epiretinal membrane (n = 1), and dislocation of neurosensory retina-choroid-RPE free graft (n = 1). CONCLUSION:Combined autologous RPE-choroid and neurosensory retinal free graft is a potential surgical alternative in eyes with end-stage exudative age-related macular degeneration, including concurrent refractory macular hole.

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The Retinome - defining a reference transcriptome of the adult mammalian retina/retinal pigment epithelium.

Project description:BACKGROUND: The mammalian retina is a valuable model system to study neuronal biology in health and disease. To obtain insight into intrinsic processes of the retina, great efforts are directed towards the identification and characterization of transcripts with functional relevance to this tissue. RESULTS: With the goal to assemble a first genome-wide reference transcriptome of the adult mammalian retina, referred to as the retinome, we have extracted 13,037 non-redundant annotated genes from nearly 500,000 published datasets on redundant retina/retinal pigment epithelium (RPE) transcripts. The data were generated from 27 independent studies employing a wide range of molecular and biocomputational approaches. Comparison to known retina-/RPE-specific pathways and established retinal gene networks suggest that the reference retinome may represent up to 90% of the retinal transcripts. We show that the distribution of retinal genes along the chromosomes is not random but exhibits a higher order organization closely following the previously observed clustering of genes with increased expression. CONCLUSION: The genome wide retinome map offers a rational basis for selecting suggestive candidate genes for hereditary as well as complex retinal diseases facilitating elaborate studies into normal and pathological pathways. To make this unique resource freely available we have built a database providing a query interface to the reference retinome 1.

| S-EPMC512282 | biostudies-literature

The retina and retinal pigment epithelium differ in nitrogen metabolism and are metabolically connected.

Project description:Defects in energy metabolism in either the retina or the immediately adjacent retinal pigment epithelium (RPE) underlie retinal degeneration, but the metabolic dependence between retina and RPE remains unclear. Nitrogen-containing metabolites such as amino acids are essential for energy metabolism. Here, we found that 15N-labeled ammonium is predominantly assimilated into glutamine in both the retina and RPE/choroid ex vivo [15N]Ammonium tracing in vivo show that, like the brain, the retina can synthesize asparagine from ammonium, but RPE/choroid and the liver cannot. However, unless present at toxic concentrations, ammonium cannot be recycled into glutamate in the retina and RPE/choroid. Tracing with 15N-labeled amino acids show that the retina predominantly uses aspartate transaminase for de novo synthesis of glutamate, glutamine, and aspartate, whereas RPE uses multiple transaminases to utilize and synthesize amino acids. Retina consumes more leucine than RPE, but little leucine is catabolized. The synthesis of serine and glycine is active in RPE but limited in the retina. RPE, but not the retina, uses alanine as mitochondrial substrates through mitochondrial pyruvate carrier. However, when the mitochondrial pyruvate carrier is inhibited, alanine may directly enter the retinal mitochondria but not those of RPE. In conclusion, our results demonstrate that the retina and RPE differ in nitrogen metabolism and highlight that the RPE supports retinal metabolism through active amino acid metabolism.

| S-EPMC7039560 | biostudies-literature

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