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PubMed1984

Age-related changes in the retinal pigment epithelium of pigmented rats.

A number of significant age-related changes were found to occur in the retinal pigment epithelium (RPE) of normal pigmented ACI rats. Age-related morphological changes in the RPE included: changes in RPE cell height, an increase in lipofuscin content, alterations in the apical microvilli and basal infoldings, and an apparent thickening of the RPE basal lamina. Unusual banded structures were often seen within the basal infoldings of the RPE in senescent but not in young adult rats. Lipid droplets were relatively common in the RPE of senescent rats, but were quite rare in 4- and 11-month-old animals. In addition, contact between the RPE apical microvilli and the photoreceptor outer segments appeared to become less intimate with age. Phagocytosis of rod outer segment discs appeared to be reduced between 4 and 32 months of age. This reduction was greater than could be accounted for solely by a concomitant age-related decrease in the number of photoreceptors per unit retinal length. RPE-choroid acid phosphatase activity (a lysosomal marker), on the other hand, did not appear to change with age. The molar ratio of vitamin A-palmitate to vitamin A-stearate in the PRE-choroid rose significantly with age, from about 1.85 at both 4 and 11 months, to over 2.5 at 28 months. At each age, the palmitate- to stearate-ester ratio was the same in the dark-adapted and light-adapted eyes.

Acid Phosphatase↗
PubMed2006

Pigment epithelium-derived factor protects retinal pigment epithelium from oxidant-mediated barrier dysfunction.

Retinal pigment epithelium (RPE) cells form a monolayer at the blood-retina barrier between the retina and choriocapillaries. The barrier function may be damaged by multiple stresses to the cell, including the repeated exposure to oxidants that are generated by photoreceptor cell turnover. The purpose of our study was to document the protective effect of pigment epithelium-derived factor (PEDF), a tropic factor produced by the RPE, on H(2)O(2)-induced RPE barrier dysfunction. When assayed by a FITC-labeled dextran transepithelial flux, the increased permeability of the RPE barrier (induced by H(2)O(2)) was prevented by PEDF pretreatment. To further explore the mechanism leading to this permeability change, we investigated the distribution of cytoskeleton and junctional proteins. The redistribution of the two junctional proteins occludin, and N-cadherin and actin reorganization in RPE, induced by H(2)O(2), can be prevented by PEDF pretreatment. PEDF can also prevent H(2)O(2)-induced stress kinase p38/27-kDa heat shock protein signaling which is known to mediate actin rearrangement. These findings indicated that PEDF can stabilize actin, maintain normal membrane occludin and N-cadherin structure, and preserve the barrier function of RPE cells against oxidative stress.

Actins↗
PubMed2004

Pigment epithelium-derived factor in the monkey retinal pigment epithelium and interphotoreceptor matrix: apical secretion and distribution.

Pigment epithelium-derived factor (PEDF) is an extracellular protein derived from the retinal pigment epithelium (RPE), a tissue formed by polarized cells that release growth and trophic factors in a directional fashion. We have investigated the distribution and directional release of PEDF protein by the monkey RPE. We established primary cultures of monkey RPE cells that expressed the PEDF gene, and that synthesized and secreted the PEDF protein. Northern analysis of RPE cultures and monkey ocular tissues showed that PEDF transcripts were highly expressed in RPE as compared with several other monkey ocular tissues, being even more abundant in cultured cells than they were in the native RPE. The differentiated RPE cells in culture secreted protein that shared the immunological, biochemical and biological characteristics of PEDF. The overall PEDF levels in the RPE conditioned media reached 6.5 mg ml- after 8 days in culture (i.e. 1.1 pg of PEDF per RPE cell). RPE cells were cultivated on permeable supports as monolayers forming a barrier between apical and basal compartments. Apical and basal culture media were sampled at three or four-day intervals for 18 cycles, and the PEDF content was quantified. Most of the PEDF protein was significantly higher in the apical than in the basal medium (>4 times) at the initial recovery intervals, to be detected only in the apical medium at the latter intervals. In the native monkey eye, the concentration of soluble PEDF in the interphotoreceptor matrix (144 nM) was 7-fold and 25-fold greater than in vitreous and aqueous, respectively. PEDF was abundant in the interphotoreceptor matrix surrounding rod and cone outer segments, and was detectable at lower levels in the RPE as visualized by confocal microscopy. We concluded that PEDF synthesized by the RPE is secreted preferentially from the apical surface and is distributed apically to the RPE bordering the outer segments of photoreceptors. PEDF can be a useful marker for RPE polarization and differentiation. The polarization of RPE may be an important mechanism to control PEDF secretion and our results offer interesting possibilities on regulation of PEDF.

Animals↗
PubMed2005

Vitamin A up-regulates the expression of thrombospondin-1 and pigment epithelium-derived factor in retinal pigment epithelial cells.

Vitamin A is essential for the visual system. It is metabolized in the retina and the resulting product, retinoic acid (RA), greatly affects the structure and functions of retinal pigment epithelial (RPE) cells. RPE cells produce a variety of extracellular matrix (ECM) proteins and angiogenic factors, both of which are expressed at varying levels in the normal RPE layer. In this study, we investigated the effect of all-trans-retinoic acid on the production of an ECM protein, thrombospondin-1 (TSP-1), and two angiogenic factors, pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) by RPE cells. RA increased the release of TSP-1 and PEDF, but not that of VEGF, from human RPE cells in vitro. In vitamin A-deficient mice, the expression of TSP-1 and PEDF in the RPE layer considerably decreased compared with that of normal control mice. The vitamin A deficiency hardly affected the accumulation of VEGF in the RPE layer. These findings suggest that vitamin A modulates the structure and anti-angiogenic functions of the RPE layer partly by up-regulating the expression of the angiogenesis-related ECM protein, TSP-1, and the anti-angiogenic factor, PEDF.

Animals↗
PubMed2006

Pigment epithelium-derived factor inhibits oxidative stress-induced cell death by activation of extracellular signal-regulated kinases in cultured retinal pigment epithelial cells.

Oxidative stress-induced retinal pigment epithelial (RPE) cell death is involved in the pathogenesis of age-related macular degeneration (AMD). Pigment epithelium-derived factor (PEDF) is an anti-angiogenic/neurotropic dual functional factor, and recently it was also shown to mediate anti-oxidative action. In the present study, the influence of PEDF in hydrogen peroxide (H(2)O(2))-induced RPE cell death was investigated using nontransformed human RPE cell line (ARPE-19). The recombinant PEDF was purified from E. coli. The MTT cell viability assay showed that PEDF rescued ARPE-19 from H(2)O(2)-induced cell death in a dose- and time-dependent manner. Western blot analysis revealed that PEDF stimulated the extracellular signal-regulated kinases (ERK1/2) phosphorylation. The PEDF cytoprotective effect was significantly attenuated by the ERK1/2 inhibitor PD98059. In this study, we demonstrate that PEDF induces ERK1/2 phosphorylation and we further suggest that the ERK signal cascade contributes to RPE cell's cytoprotection against oxidative stress.

Cell Line↗
PubMed2006

Developmental changes in antioxidant metabolites, enzymes, and pigments in fruit exocarp of four tomato (Lycopersicon esculentum Mill.) genotypes: beta-carotene, high pigment-1, ripening inhibitor, and 'Rutgers'.

In surface cell layers of fleshy fruit, antioxidants must limit photooxidative reactions that generate reactive oxygen species (ROS) in high light. Our objective was to measure changes in the concentrations of antioxidant metabolites and pigments, and the activities of enzymes of the Mehler-peroxidase, ascorbate-glutathione cycle in fruit exocarp tissue under non-stress conditions of the following fruit-specific tomato (Lycopersicon esculentum Mill.=Solanum lycopersicum) mutants and their parent: (1) beta-carotene (B), (2) high pigment (hp-1), (3) ripening inhibitor (rin), and (4) the nearly isogenic wild-type 'Rutgers'. Developmental variables included days after anthesis (DAA) and fruit surface color. The highest total ascorbic acid (AsA) concentration was in the exocarp of immature green fruit of hp-1, being 32% higher than 'Rutgers'. The hp-1 mutant also had the highest chlorophyll and total carotenoid concentrations, comprised mostly of lycopene in red ripe fruit; whereas, beta-carotene comprised 90% of the carotenoids in B. Although enzyme activities varied within genotype, they generally increased with development, then decreased as fruit maturity was reached, being coupled with AsA and glutathione (GSH) concentrations. In all mutants, dark-green (DG) exocarp had more chlorophyll and protein, higher concentrations of reduced AsA and GSH, and usually lower enzyme activities than light-green (LG) exocarp taken from the same fruit.

Antioxidants↗
PubMed2003

Vascular endothelial growth factor upregulates pigment epithelium-derived factor expression via VEGFR-1 in human retinal pigment epithelial cells.

We previously demonstrated that differentiated retinal pigment epithelial (RPE) cells express high levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF), and a critical balance between VEGF and PEDF is important to prevent the development of choroidal neovascularization. We report here that VEGF secreted by RPE cells upregulates PEDF expression via VEGFR-1 in an autocrine manner. PEDF mRNA and protein expression was downregulated by neutralizing antibody against VEGF in differentiated human RPE cells. VEGFR-1 neutralization decreased PEDF mRNA and protein expression whereas anti-VEGFR-2 antibody had no effect. Addition of placenta growth factor (PlGF) restored PEDF expression in the presence of anti-VEGF antibody. These results demonstrate a regulatory interaction between angiogenesis stimulators and inhibitors to maintain homeostasis in normal human retina.

Cells, Cultured↗
PubMed2001

Fluorescent pigments of the retinal pigment epithelium and age-related macular degeneration.

The major hydrophobic fluorophore of the retinal pigment epithelium (RPE) is A2E, a pyridinium bis-retinoid derived from all-trans-retinal and phosphatidyl-ethanolamine. The accumulation of fluorophores such as A2E is implicated in the pathogenesis of age-related macular degeneration (AMD), a disease associated with the deterioration of central vision and a leading cause of blindness in the elderly. Recent chemical and biological studies have provided insight into the synthesis and biosynthesis of A2E, the spectroscopic properties of this pigment, and the role of A2E and RPE cell death.

Age Factors↗
PubMed1997

Peropsin, a novel visual pigment-like protein located in the apical microvilli of the retinal pigment epithelium.

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.

Amino Acid Sequence↗
PubMed2006

The other pigment cell: specification and development of the pigmented epithelium of the vertebrate eye.

Vertebrate retinal pigment epithelium (RPE) cells are derived from the multipotent optic neuroepithelium, develop in close proximity to the retina, and are indispensible for eye organogenesis and vision. Recent advances in our understanding of RPE development provide evidence for how critical signaling factors operating in dorso-ventral and distal-proximal gradients interact with key transcription factors to specify three distinct domains in the budding optic neuroepithelium: the distal future retina, the proximal future optic stalk/optic nerve, and the dorsal future RPE. Concomitantly with domain specification, the eye primordium progresses from a vesicle to a cup, RPE pigmentation extends towards the ventral side, and the future ciliary body and iris form from the margin zone between RPE and retina. While much has been learned about the molecular networks controlling RPE cell specification, key questions concerning the cell proliferative parameters in RPE and the subsequent morphogenetic events still need to be addressed in greater detail.

Animals↗
PubMed2005

Pigment-epithelium-derived factor is upregulated in photocoagulated human retinal pigment epithelial cells.

There is much evidence that pigment-epithelium-derived factor (PEDF) is a potent antiangiogenic cytokine which inhibits retinal and choroidal neovascularization by inducing apoptosis in activated vascular endothelial cells. Furthermore, the regulation of PEDF appears to be linked to the regulation of vascular endothelial growth factor (VEGF), one of the most potent inducers of intraocular neovascularization. Previous studies have established that thermal photocoagulation, the mainstay in the therapy of various neovascular diseases of the posterior segment, results in a decrease in intraocular concentrations of VEGF and other angiogenic growth factors, thereby inhibiting active retinal neovascularization. In the current study, we sought to determine whether thermal photocoagulation has the potential to regulate the expression of PEDF in human retinal pigment epithelial (RPE) cells. Cultures of RPE cells were photocoagulated with a 532-nm diode laser. Subsequently, RNA was isolated for RT-PCR, and whole-cell extracts and precipitated cell culture supernatant were subjected to Western blot analysis. According to our results, PEDF mRNA and protein are significantly upregulated after photocoagulation. Moreover, PEDF protein was found to be secreted in the cell culture medium.

Blotting, Western↗
PubMed2000

Pigment epithelium-derived factor supports normal development of photoreceptor neurons and opsin expression after retinal pigment epithelium removal.

Dysfunction of the retinal pigment epithelium (RPE), its loss, or separation from the underlying neural retina results in severe photoreceptor degeneration. Pigment epithelium-derived factor (PEDF) is a glycoprotein with reported neuroprotective and differentiation properties that is secreted in abundance by RPE cells. The "pooling" of PEDF within the interphotoreceptor matrix places this molecule in a prime physical location to affect the underlying neural retina. The purpose of this study was to analyze the morphogenetic activity of PEDF in a model of photoreceptor dysmorphogenesis induced by removal of the RPE. Eyes were dissected from embryonic Xenopus laevis, and the RPE was removed before culturing in medium containing PEDF, PEDF plus anti-PEDF antibodies, or medium alone. Control retinas were maintained with an adherent RPE. Light and electron microscopic analysis was used to examine retinal ultrastructure. Opsin was localized immunocytochemically and quantified as an index of outer segment membranous material and photoreceptor protein expression. Removal of the RPE resulted in an aberrant assembly of photoreceptor outer segments, loss of fine subcellular ultrastructure in photoreceptors, and a reduction in opsin protein levels when compared with control retinas. The addition of PEDF prevented the dysmorphic photoreceptor changes induced by RPE removal. In particular, photoreceptor ultrastructure, outer segment membrane assembly, and steady-state levels of opsin were equivalent to control conditions. Anti-PEDF antibodies completely blocked the morphogenetic activity of PEDF. These results indicate that PEDF is able to mimic the supportive role of the RPE on photoreceptors during the final stages of retinal morphogenesis.

Animals↗
PubMed2003

[Downregulation of the pigment epithelium derived factor by hypoxia and elevated glucose concentration in cultured human retinal pigment epithelial cells].

OBJECTIVE: To explore the effect of hypoxia and high glucose concentration on the production and secretion of vascular endothelial growth factor (VEGF) and pigment epithelium derived factor (PEDF), an antiangiogenesis factor, in the cultured human retinal pigment epithelium (RPE) cells. METHODS: Human RPE cells were cultured under normoxic or hypoxic (1% O(2)) condition with or without (25 mmol/L) glucose. RT-PCR and real-time quantificaton analysis were used to examine the expression of VEGF and of PEDF mRNAs. Western blot analysis was used to measure the levels of VEGF and PEDF proteins. RESULTS: The expression of VEGF mRNA in RPE cells under hypoxic condition for 12 hours was 2.6 times that under the normoxic condition (P = 0.001), and the expression of PEDF mRNA was only 0.77 time that of the controls (P = 0.251). Under hypoxic condition with high concentration of glucose the expression of VEGF mRNA in RPE cells was 3.8 times that under the normoxic condition (P < 0.001), and the expression of PEDF mRNA was further decreased (only 0.23 time that of the controls, P = 0.02). The expression levels of VEGF protein under hypoxic condition with and without glucose were 1.69 and 1.27 times respectively those under the normoxic condition (P < 0.0001 and P = 0.004). The expression level of PEDF protein under hypoxic condition with glucose was 0.49 time that under the normoxic condition (P < 0.0001) and the expression level of PEDF protein under hypoxic condition without glucose was 0.92 time that under the normoxic condition (P = 0.114). CONCLUSION: Hypoxia indirectly influence the downregulation of PEDF and high concentration of glucose directly downregulates the expression of PEDF and increases the expression of VEGF simultaneously, thus supporting the concept that hyperglycemia is one of the most dangerous consequences of diabetes-associated "glucose toxicity" in vivo.

Blotting, Western↗
PubMed1989

Carney's complex of primary pigmented nodular adrenocortical disease and pigmentous and myxomatous lesions.

A complex of primary pigmented nodular adrenocortical hyperplasia associated with myxomatous masses and pigmented lesions of the skin was recently described by Carney. Herein, we describe three patients with Carney's complex seen at our institution. Two patients presented with Cushing's syndrome and one patient with atrial myxoma. The diagnosis was revealed in all three because of an awareness of the disease in association with primary adrenocortical hyperplasia. Because Cushing's syndrome and atrial myxomas are life-threatening components of the disease and can occur metachronously, an early diagnosis in combination with the appropriate treatment is mandatory, and follow-up measures should be taken to define the natural course of events in the disease.

Adrenal Cortex↗
PubMed1989

Retinal light damage reduces autofluorescent pigment deposition in the retinal pigment epithelium.

Lipofuscin in the retinal pigment epithelium (RPE) is thought to be derived from phagocytosed photoreceptor outer segment disc membranes. Based on this hypothesis, one would predict that the rate of lipofuscin deposition in the RPE would be proportional to the density of photoreceptor cells in the retina. In previous studies it was demonstrated that specific loss of photoreceptor cells due to a genetic defect resulted in a substantial decrease in the rate of age-related lipofuscin accumulation in the RPE. In order to confirm that this decreased RPE lipofuscin deposition was directly related to reduced photoreceptor cell density, experiments were conducted to determine whether light-induced photoreceptor cell destruction affected RPE lipofuscin content. The effects of retinal light damage on RPE autofluorescent pigment accumulation resulting from both normal aging and vitamin E deficiency were examined. Starting immediately after weaning, albino Fisher 344 rats were fed diets either containing or lacking vitamin E. All animals were maintained on a 12 hr/12 hr light/dark cycle. During the light phases of the cycles, the cage illuminance for one-half the animals in each dietary group was 750 lux, while the remaining rats were exposed to a light level of 15 lux. Illumination was provided by 40 watt cool-white fluorescent lamps. After 17 weeks, rats in both dietary groups that were maintained under the higher light intensity had substantially reduced photoreceptor cell densities relative to animals in the same dietary group maintained under dim light conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1998

Involvement of calcium in retinal pigment epithelial cell proliferation and pigmentation.

PURPOSE: The aim of this study is to explore the role of intracellular calcium in the mechanism of co-regulation of retinal pigment epithelial cells (RPE) by vitreous fluid and platelet mitogens, in order to evaluate the use of calcium modulating drugs in preventing RPE cell proliferation and contraction of fibrocellular membranes. METHODS: Monolayers of human RPE cells were loaded with Fura-2-AM and examined in a fluorimeter for changes in intracellular free calcium in response to platelet mitogens (PDGFAB or TGFbeta1) and vitreous fluid (containing vitreous substrate proteins), both alone or in combination. The effect of the calcium antagonists TMB8 and verapamil and the calmodulin antagonists J8 and tamoxifen were then examined on RPE cell proliferation and pigmentation, both in the presence and absence of vitreous substrate and platelet mitogens. RESULTS: We report that co-exposure of RPE cells to platelet mitogens and vitreous fluid produces an increase in intracellular free calcium of greater duration than that with either PDG-FAB, TGFbeta1 or vitreous fluid alone. Calcium and calmodulin antagonists significantly reduce RPE cell proliferation in both the presence and absence of vitreous substrate and platelet mitogens. Calcium antagonists also stimulate the accumulation of autofluorescent granules within RPE cells. CONCLUSIONS: Calcium signalling plays a role in the co-regulation of RPE cells by vitreous substrate and platelet mitogens. Drugs that lower intracellular calcium or inhibit calmodulin may offer an additional approach to preventing the hyperproliferation of RPE cells in PVR.

Adult↗
PubMed2006

Use of iris pigment epithelium to replace retinal pigment epithelium in age-related macular degeneration: a gene expression analysis.

OBJECTIVE: To determine the gene expression profiles of primary retinal pigment epithelium (RPE) and iris pigment epithelium (IPE) using microarrays. METHODS: Primary RPE and IPE from 6 human donor eyes were collected, and total RNA was isolated. Differences in gene expression were determined using a human genechip (human U95Av2 [12 600 probes]; Affymetrix Inc, Santa Clara, Calif). RESULTS: Hierarchical cluster analysis differentiated the gene expression profiles of RPE and IPE clusters into 2 distinct groups. A mean +/- SD of 5308 +/- 416 gene probes were expressed in RPE vs 6130 +/- 205 in IPE. Sixty-eight genes were expressed only in RPE; 154 genes were expressed only in IPE. Twenty-two additional genes had greater than 3-fold increased expression in RPE vs IPE, and 147 genes had greater than 3-fold decreased expression in RPE vs IPE. CONCLUSION: There are major differences in the gene expression profiles of primary RPE vs IPE. Clinical Relevance The different gene expression profiles of primary RPE vs IPE harvested from the same donor eyes infer that it may be difficult for IPE to replace all aspects of damaged RPE function in transplantation studies.

Aged↗
PubMed1996

The properties of retinal pigment epithelial cells in proliferative vitreoretinopathy compared with cultured retinal pigment epithelial cells.

Retinal pigment epithelial (RPE) cells, which proliferate and dedifferentiate under several pathological conditions, and cultured RPE cells have been considered a good model for comparison. In this investigation, we compared the properties of RPE cells in proliferative vitreoretinopathy with that of cultured human RPE cells. mRNAs of RPE cells from patients with proliferative vitreoretinopathy and from cultured human RPE cells were extracted, and reverse transcriptase-polymerase chain reaction was performed. We also examined cells that were aspirated from bare RPE surface from a patient with a giant retinal tear. We amplified the interleukin-6 gene in the proliferative membranes and cultured RPE cells. We also amplified the tyrosinase gene in seven of eight proliferative membranes, as well as tyrosinase-related proteins and cellular retinaldehyde-binding protein genes, but not the tyrosinase gene in cultured RPE cells. The cells aspirated from bare RPE surface showed reduced activity for expressing interleukin-6 and tyrosinase genes. The dedifferentiation characteristics of cultured RPE cells were different, in that they were less active than RPE cells in proliferative membranes for expressing the genes of melanogenesis, which are essential for pigment cells. Interleukin-6 and genes that were related to melanogenesis were expressed in the proliferative membranes and may play an important role in the generation of proliferative vitreoretinopathy.

Actins↗