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(Investigative Ophthalmology and Visual Science. 2001;42:1646-1652.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

In Vivo Protection of Photoreceptors from Light Damage by Pigment Epithelium–Derived Factor

Wei Cao1, Joyce Tombran-Tink2, Rajesh Elias1, Steven Sezate1, David Mrazek2 and James F. McGinnis1

1 From the Department of Ophthalmology, Health Science Center, Dean McGee Eye Institute, University of Oklahoma, Oklahoma City; and the 2 Department of Pharmaceutical Sciences, University of Missouri-Kansas City.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To determine whether pigment epithelium–derived factor (PEDF) exhibits neurotrophic and neuroprotective activities in vivo for photoreceptor cells.

METHODS. Sprague-Dawley albino rats were injected intravitreally with 2 µg PEDF or a mixture of 1 µg basic fibroblast growth factor (bFGF)/1 µg PEDF in a volume of 1 µl phosphate-buffered saline (PBS). Animals were exposed to constant light for different periods at an illuminance level of 1200 to 1500 lux. The electroretinogram (ERG) waveforms of both eyes in the same animal were simultaneously recorded to evaluate functional protection. The morphologic protection was evaluated by quantitative histology.

RESULTS. Intravitreal injection of PEDF before exposure to constant light resulted in significant morphologic and functional protection of photoreceptor cells in the retina of light-damaged rats. This protection depended on the duration and severity of light damage. The protection was eliminated by extending the light exposure to 10 days. Injection of PEDF at 0, 1, and 2 days after constant light exposure did not provide significant protection above that seen in PBS-injected eyes. Combination of PEDF with bFGF improved functional protection of photoreceptor cells.

CONCLUSIONS. The data demonstrate that PEDF protected photoreceptor cells against light damage. This is significant, because it may open new avenues for the study of molecular mechanisms underlying degenerative processes. This, in turn, may lead to the development of therapeutic strategies for the prevention and treatment of degenerative diseases of the retina.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Photoreceptor cell death is an irreversible event in many blinding diseases, including retinitis pigmentosa, age-related macular disease, and retinal detachment. With the inherent vulnerability of photoreceptor cells, it is not surprising that many different mutations and acquired insults lead to photoreceptor cell death.1 In postmitotic photoreceptor cells, there is a significant increase in cell death when metabolic activity in the retina increases.2 This, together with the high focal concentrations of mitochondria in photoreceptors and the very high blood supply to the choriocapillaris, suggests that there may be very little reserve in the energy supply to photoreceptor cells. The complex interrelationships among photoreceptors, Müller cells, and retinal pigment epithelium (RPE) add to visual vulnerability, in that failure of other cell types readily leads to secondary loss of rods and cones. It seems possible that photoreceptor cells live on a knife’s edge, and that relatively mild insults can significantly increase the probability of cell death. Conversely, a relatively modest benefit to the cell may reduce the chances of cell death sufficiently to have an important clinical impact.

An enhancement of photoreceptor survival can be produced by the injection of survival factors.3 The first in vivo experimental success of the therapeutic use of growth factors in photoreceptor rescue was the use of basic fibroblast growth factor (bFGF) in the Royal College of Surgeons (RCS) rat which has an inherited defect in the pigment epithelial cells that results in retinal degeneration. Although the sham-injected eyes displayed localized photoreceptor rescue, there was significantly more survival when bFGF was injected into the vitreal or subretinal spaces.4 In the light-damaged model of retinal degeneration, a high degree of photoreceptor rescue was present with bFGF.5 However, bFGF is a mitogen that has been shown to increase the proliferation of some RPE and Müller glial cells in the retina, and these effects may restrict the therapeutic use of bFGF in the treatment of retinal degeneration.

Pigment epithelium-derived factor (PEDF), a 50-kDa glycoprotein, was first isolated from medium conditioned by human fetal retinal pigment epithelial (RPE) cells and was shown to be made in vivo by both fetal and adult RPE cells. After release from the RPE, PEDF binds to the glycosaminoglycans of the interphotoreceptor matrix,6 7 placing it in a prime physical location to affect the underlying neural retina. The PEDF gene has been cloned, sequenced, and shown to have a tight linkage with a retinitis pigmentosa locus (RP13) on chromosome 17p13.3, making it a candidate gene for this form of retinal degeneration.8 9 10 It has been reported that PEDF supports normal development of photoreceptor neurons and opsin expression after RPE removal.11 PEDF acts as a survival factor for cultured cerebellar granule cells,12 13 14 spinal motor neurons,15 16 and hippocampal neurons.17 Recently, we demonstrated the survival-promoting activity of PEDF on retinal neurons against hydrogen peroxide–induced cell death in vitro.18 In addition to its effects on neurons, PEDF is a potent antiangiogenesis factor19 and is considered to be a key coordinator of retinal neuronal and vascular functions.20

With the light-dependent degeneration of rat photoreceptor cells serving as a model system, our data demonstrate that the intravitreal injection of PEDF resulted in significant protection of photoreceptor cells. When PEDF was used in combination with bFGF, there was an enhancement of the functional status of the photoreceptor cells beyond the protection provided by either factor alone. This activity in combination with its antiangiogenic properties may make PEDF an important agent in the development of treatment strategies for degenerative disorders.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Sprague-Dawley albino rats were obtained at 2 to 5 months of age and maintained in our cyclic light environment (12 hours on, 12 hours off, at an in-cage illuminance of <250 lux) for 10 or more days before use. All experimental procedures adhered to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and the University of Oklahoma Faculty of Medicine Guidelines for Animals in Research.

Intravitreal Injection and Constant Light Exposure
Rats were anesthetized with a ketamine (80 mg/kg)-xylazine (6 mg/kg) mixture and then were administered intravitreally 2 µg PEDF, 1 µg bFGF, or a mixture of 1 µg PEDF/1 µg bFGF in a volume of 1 µl phosphate-buffered saline (PBS). The concentration of bFGF at 1 µg/µl was based on publications by Faktorovich et al.4 5 and LaVail et al.21 PEDF (1 or 2 µg/µl) used in this study was chosen based on the known effective dose (1 µg/µl) of PEDF in delaying photoreceptor death in a mouse model.22 PEDF was purified by high-performance liquid chromatography from conditioned medium obtained from human fetal RPE cells. Polyclonal antibodies, generated against the native human PEDF protein, specifically recognize a single protein migrating at 50 kDa on Western blot analysis of both one- and two-dimensional gels.6 12 Human recombinant bFGF was purchased from R&D Systems (Minneapolis, MN). The injections were made using a 30-gauge needle inserted through the sclera, choroid, and retina, approximately midway between the ora serrata and equator of the eyeball. To simplify manipulations and to avoid errors, it was arbitrarily decided that the left eye would be used as a sham-operation control (PBS-injected) and the right eye subjected to either PEDF, bFGF, or the PEDF/bFGF mixture. Depending on the experiment, animals were exposed to constant light for progressive periods of time (3, 7, 10, and 14 days). Constant light at an illuminance level of 1200 to 1500 lux was provided by two 40-W white fluorescent light bulbs (commercially available) that were suspended 50 cm above the floor of the cage. During light exposure, rats were maintained in transparent polycarbonate cages with stainless-steel wire bar covers. A water bottle is kept in the appropriate depression in the cage cover, but food is placed in the bottom of the cage on the bedding.

Functional Evaluation of Photoreceptor Cell Rescue by Electroretinogram
Animals were kept in total darkness for a minimum of 60 minutes before electroretinograms (ERGs) were recorded.23 Pupils were dilated with 1% atropine and 2.5% phenylephrine HCl. Animals were anesthetized intramuscularly with a ketamine-xylazine mixture. ERG responses were recorded with a silver chloride needle electrode placed in the cornea with 1% tetracaine topical anesthesia. A reference electrode was positioned at the nasal fornix, and a ground electrode on the foot. The duration of light stimulation was 10 msec. The band pass was set at 0.3 to 500 Hz. Fourteen responses were averaged, with flash intervals of 20 seconds. For quantitative analysis, the B-wave amplitude was measured between A- and B-wave peaks. The ERG waveforms of both eyes in the same animal were simultaneously recorded and compared as the right-to-left–eye ratio of B-wave amplitude.

Morphologic Evaluation of Photoreceptor Rescue by Quantitative Histology
According to previously published procedures,4 5 21 animals were killed by an overdose of carbon dioxide after ERG testing. The eyes were enucleated, fixed, and embedded in paraffin, and 5-µm-thick sections were taken along the vertical meridian to allow comparison of all regions of the eye. In each of the superior and inferior hemispheres, outer nuclear layer (ONL) thickness was measured at nine defined points. Each point was centered on adjacent 450-µm lengths of retina. The first point of measurement was located approximately 450 µm from the optic nerve head, and subsequent points were located more peripherally. In addition to mean ONL thickness for the entire retinal section, ONL thickness of the region of retina most sensitive to the damaging effects of light was compared among different groups of rats. In each of the experiments in which ONL thickness was quantified, a single section from the retinas of at least 6 (usually 10 or more) eyes was measured.

Statistical Analysis
Results are expressed as mean ± SD. Differences were assessed by one-way ANOVA. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Morphologic evaluation of photoreceptor cell rescue was performed by quantitative histology. One week of exposure to fluorescent light (1200–1500 lux) reduced the thickness of the ONL of photoreceptor cell nuclei from the normal 9 to 11 rows (35–40 µm; Fig. 1A ) to 1 to 3 rows (5–10 µm) in the most degenerated region of the uninjected eye (Fig. 1B) or the PBS-injected sham control (Fig. 1C) . Light exposure almost completely eliminated the inner segments (ISs) and outer segments (OSs) of most photoreceptors in this region. However, in PEDF-injected eyes, there was significant rescue of photoreceptors, with the ONL having six to seven rows (25–30 µm) of nuclei, although many cells had swollen (ISs) and disorganized OS profiles (Fig. 1D) .



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  		Figure 1. PEDF protection of photoreceptor cells from light-dependent degeneration. (A) Photomicrograph of a retina from a normal uninjected rat reared in cyclic light. The ONL consisted of 9 to 11 rows of photoreceptor cell nuclei. Retinas from (B) an uninjected eye and from eyes injected with (C) PBS or (D) PEDF 2 days before a 1-week exposure to constant light. Scale bar, 20 µm. GCL, ganglion cell layer; INL, inner nuclear layer.

 
ERG was used to test the ability of PEDF to protect retinal function, and representative data from these studies (Fig. 2) demonstrated that constant light for 7 days completely eliminated the ERG response, whereas PEDF, injected 2 days before constant light exposure, provided significant functional rescue. Therefore, the morphologic data (Figs. 1A 1B 1C 1D) were indicative of the functional status (Fig. 2) of the retinas. The ability of PEDF to promote the survival of photoreceptor cells when injected at various times before, or after, exposure to light was also investigated (Fig. 3) . The control retinas of albino rats reared in cyclic light had a mean ONL thickness of 38 µm, and injection of PBS or PEDF alone did not change this. However, in the retinas of rats exposed to continuous lighting for 7 days, the mean ONL thickness was reduced to 8 µm (Fig. 3B) , and in PBS-injected control retinas, the mean ONL thickness was 13 µm. Intravitreal injections of PEDF at 2 days or 1 day before exposure to constant light were equally protective, with the ONL thickness being 23 and 20 µm, respectively, whereas injection of PEDF at 0, 1, or 2 days after constant light exposure did not provide any significant protection above that seen in PBS-injected eyes. The functional data (Fig. 3A) were also consistent with these morphologic findings.



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  		Figure 2. Functional rescue as measured by ERG recordings after various treatments: First row: control cyclic light without injection. Second row: cyclic light with injection of PEDF (right eye) and PBS (left eye). Third row: 1 week of exposure to constant light without any injection. Fourth row: intravitreal injection of PEDF (right eye) and PBS (left eye) 2 days before exposure to 1 week of constant light. There was no recovery period after constant light exposure; animals were put into dark adaptation immediately after exposure. The period for dark adaptation before the ERG measurement was 60 minutes.

 


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  		Figure 3. Comparison of photoreceptor rescue by PEDF as a function of treatment time. (A) Mean right-to-left eye ratios of ERG B-wave amplitudes. *P < 0.05 versus the PBS-injected control group (n = 8). (B) Mean ONL thickness of retinas in rats maintained in cyclic light (control), exposed to constant light (CL) for 1 week, or PBS-injected before CL for 1 week and injected intravitreally with PEDF, at days 2, 1, or 0 before or at day 1 or 2 after the start of light exposure. *P < 0.05 versus the PBS-injected control group (n = 10).

 
To assess the damage to photoreceptor cells during exposure to constant light for various lengths of time and to determine whether PEDF pretreatment was equally effective in preventing the death of photoreceptor cells during these periods, animals were exposed to constant light for 3, 10, and 14 days, with or without PEDF injected 2 days before light exposure. The data from these experiments are presented in Figure 4 . After 3 days of constant light, the ONL thickness in the posterior-to-equatorial region of the superior hemisphere was reduced to 3 to 5 rows (Fig. 4D) , compared with the normal 9 to 11 rows (Fig. 1A) . PEDF preserved eight to nine rows of photoreceptor nuclei (Fig. 4A) . Exposure to constant light for 10 days left only one to two rows of nuclei (Fig. 4E) , whereas pretreatment with PEDF resulted in retention of four to five rows (Fig. 4B) . The eyes exposed to constant light for 14 days had the most severe degeneration with a greater loss of photoreceptor nuclei throughout the retina, and only one row of photoreceptor nuclei remaining in the posterior to equatorial region of the superior hemisphere (Fig. 4F) . PEDF pretreatment (Fig. 4C) did not notably protect photoreceptor cells in this group.



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  		Figure 4. Comparison of photoreceptor rescue by PEDF as a function of constant light-exposure time. All animals were injected intravitreally with either PEDF or PBS 2 days before light exposure. PEDF-injected eyes exposed to constant light for (A) 3, (B) 10, and (C) 14 days. PBS-injected eyes exposed to constant light for (D) 3, (E) 10, and (F) 14 days. GCL, ganglion cell layer; INL, inner nuclear layer.

 
A summary of the ERG data from all the animals in each treatment group can be presented as the ratio of the B-wave in the PEDF-injected eye (right) to the B-wave in the control PBS-injected eye (left) in the same animal (Fig. 5) . The ERG B-wave ratio was more than three times higher in the 3-day light-damage group, 2.5 times higher in the 7-day group, and approximately 2 times higher in the 10-day group, and there was no significant improvement in function in the 14-day-exposure group. It is known that rod OS can, with time, regenerate after sublethal light damage to photoreceptors.24 25 To determine whether the effects of PEDF are enhanced with time, rats were allowed to recover for 14 days in cyclic light after 7 days of constant light. After 14 days of recovery, the ONL thickness in PEDF-treated eyes (Fig. 6D) was similar to the ONL thickness in eyes without any recovery period (Fig. 1D) . However, the PEDF-treated eyes showed better morphology of the ISs and OSs after the 14 days of recovery than without any recovery time (Fig. 1D) .



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  		Figure 5. Preservation of retinal function by PEDF. Mean right-to-left eye ratios of ERG B-wave amplitudes. *P < 0.05 versus control group (n = 6).

 


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  		Figure 6. Effects of PEDF, bFGF, and PEDF/bFGF on photoreceptor cell rescue measured after a 14-day recovery time. (A) Normal retina from an uninjected eye in a rat reared in cyclic light. Insert: typical ERG waveform with an ERG B-wave amplitude of approximately 800 µV. (B–F) Eyes, exposed to constant light for 1 week followed by a 14-day recovery period in cyclic light. Injections were given 2 days before constant light exposure. Retinas are shown from (B) an uninjected eye and from (C) PBS- (D) PEDF- (E) bFGF-, and (F) PEDF/bFGF-injected eyes. GCL, ganglion cell layer; INL, inner nuclear layer.

 
Because bFGF has been shown to be extremely potent in protecting photoreceptor cells from light-mediated degeneration, it was tested in this experimental paradigm. Injection of bFGF alone (Fig. 6E) provided much better protection than PEDF alone (Fig. 6D) , but when bFGF and PEDF were applied together (Fig. 6F) , there was a slightly better preservation of rod OS morphology. As with morphology, functional rescue (ERGs) improved over time with PEDF compared with animals without a recovery period (Fig. 2) . A graphic summary of the change in ratios of the B-wave amplitudes of experimental and PBS-injected control eyes is presented in Figure 7A . These data also show some benefits of using both factors simultaneously. Light micrographs of PBS-injected retinas at low magnification clearly show a marked degree of photoreceptor rescue only near the insertion sites (Fig. 8A) , whereas the rescue in PEDF-, bFGF-, or PEDF/bFGF-injected retinas (Figs. 8B 8C 8D) extends throughout much of the superior hemisphere in the eyes.



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  		Figure 7. Measurements of morphologic and functional protection of photoreceptors. (A) Mean right-to-left eye ratios of ERG B-wave amplitudes. *P < 0.05 versus the PBS-injected control group, ¶P < 0.05 versus the PEDF-injected group, {dagger}P < 0.05 versus the bFGF-injected group (n = 10). (B) Mean ONL thickness of retinas in eyes maintained in cyclic light (control) or exposed to constant light (CL) for 1 week; sham-treated with PBS-injection before CL for 1 week (PBS+CL); and injected intravitreally with PEDF, bFGF, or PEDF/bFGF 2 days before exposure to constant light for 1 week, followed by a 14-day recovery period. *P < 0.05 versus the PBS-injected group, ¶P < 0.05 versus the PEDF-injected group (n = 10).

 


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  		Figure 8. Protection of photoreceptors by PEDF and bFGF. Retinas of rats injected intravitreally with (A) PBS, (B) PEDF, (C) bFGF, or (D) PEDF/bFGF 2 days before exposure to constant light (CL) for 1 week, followed by a 14-day recovery period. Arrows: needle insertion sites. Scale bar, 240 µm.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, PEDF played an important role in neuroprotection of photoreceptor cells, when examined using the light-dependent degeneration of rat photoreceptor cells as a model system. The light damage is produced noninvasively and the intensity and duration of the light can be varied to regulate the rate and degree of cell degeneration. The period of cell degeneration can be relatively short, from several days to 1 to 2 weeks. The experiments can be performed on commercially available rats, and the animals can be used with age-matched control animals. Therefore, the light-dependent retinal degeneration model in the albino rat provides a relatively simple, fast, and efficient system for the in vivo assessment of photoreceptor survival-promoting activity.

A PEDF receptor has been characterized by PEDF affinity column chromatography of membrane proteins from retinoblastoma and cerebellar granule cells, and this 80-kDa receptor binds to the region comprising amino acids 78-121 of PEDF.26 The precise functional role of PEDF in retinal differentiation and pathogenesis is not fully known, although it has been demonstrated that PEDF is synthesized early in the development of the human retina.7 Morphologic and biochemical changes, evident in neuronal precursor cells after treatment with PEDF, include extensive neurite outgrowth and the upregulation of neuron-specific enolase and neurofilament proteins.27 Numerous studies have documented physiological functions of PEDF in a variety of tissues including promotion of survival of cultured adult cerebellar granule cells12 and protection against glutamate-induced neurotoxicity of motor neurons,16 cerebellar granule cells,13 and hippocampal neurons.17 In addition, PEDF differentially protects immature cerebellar granule neurons against apoptosis.14 Most recently, PEDF was demonstrated to inhibit hydrogen peroxide–induced cell death in a retinal neuronal culture system18 and delayed the death of photoreceptors in mouse models of inherited retinal degeneration.22

Measuring the functional status of such eyes by ERGs before histologic assessment (Figs. 2 3) demonstrates that the light damage caused blindness that could be prevented by pretreatment with PEDF for 1 or 2 days before constant light exposure, whereas PEDF given at, or after, the onset of constant light provided little or no protection. These data indicate that PEDF must be present for a period before light exposure to prevent the death of photoreceptor cells and suggest that PEDF acts by an indirect mechanism that requires the synthesis or modification of some other molecule(s).

Although the nature of the protective effect of PEDF against injury and its relation to protection from cell death remain to be determined, it has been shown recently that PEDF protects retinal neurons against oxidative stress.18 In the same in vitro system,18 bFGF, brain-derived neurotrophic factor, and ciliary neurotrophic factor also offered protection, suggesting similar mechanisms of action. The present data on the in vivo effects of PEDF support the results and conclusions obtained in cell culture and extend them to include the demonstration that PEDF protects retinal neurons from light damage. It remains to be determined how PEDF relates to other ways of ameliorating light damage, including antioxidants, hyperthermia (heat shock proteins), calcium channel blockers, prior light-exposure history, mechanical injury, and as yet undefined genetic factors.28 29 30

The molecular mechanisms by which survival factors act are complex and may include inhibition or induction of the synthesis of themselves or others in paracrine, autocrine, and inhibitory feedback loops in various biological processes. In the retina, a special type of interaction may be necessary for normal photoreceptor function and viability, such as among photoreceptors, RPE, the intervening interphotoreceptor matrix, and the Müller glial cells. These cells and the interphotoreceptor matrix either contain, synthesize, or respond to many growth factors and cytokines. In the past several years, a number of neurotrophic factors have been shown to have survival-promoting activity in a wide range of neuronal systems, and the benefits of various combinations of neurotrophic factors in retinal degeneration have been reported.21 Among them, bFGF has been shown to be one of the most potent survival factors in preventing photoreceptor cell death in several rat models of retinal degeneration, including the light-damage model.3 However, the mitogenic and angiogenic properties of bFGF may limit its usefulness in the treatment of retinal degeneration. In a recent study, PEDF was shown to have antiangiogenic activity and to inhibit the mitogenic and angiogenic properties of bFGF.19

These observations, in combination with our data showing an added beneficial effect of PEDF with bFGF on the functional protection of photoreceptor cells suggest that these two factors together could be useful for the development of strategies for treatment and prevention of blindness due to a variety of causes. Even a modest reduction in the rate of photoreceptor cell death may lead to a significant prolongation of useful vision.


   Acknowledgements
 
The authors thank Paula Pierce and Mark Dittmar for technical support.


   Footnotes
 
Supported by National Institutes of Health Grants EY06085 and EY13050; a Jules and Doris Stein Professorship from Research to Prevent Blindness (JFM); core facilities Grant EY12190 from the National Eye Institute; and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology, University of Oklahoma, Dean McGee Eye Institute.

Submitted for publication October 5, 2000; revised February 13, 2001; accepted March 5, 2001.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Wei Cao, Department of Ophthalmology, Health Science Center, Dean McGee Eye Institute, University of Oklahoma, 608 Stanton L. Young Boulevard, Oklahoma City, OK 73104. wei-cao{at}ouhsc.edu


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  9. Tombran-Tink, J, Pawar, H, Swaroop, A, Rodriguez, I, Chader, GJ (1994) Localization of the gene for pigment epithelium-derived factor (PEDF) to chromosome 17p13.1 and expression in cultured human retinoblastoma cells Genomics 19,266-272[Medline][Order article via Infotrieve]
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  14. Araki, T, Taniwaki, T, Becerra, SP, Chader, GJ, Schwartz, JP (1998) Pigment epithelium-derived factor (PEDF) differentially protects immature but not mature cerebellar granule cells against apoptotic cell death J Neurosci Res 53,7-15[Medline][Order article via Infotrieve]
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