This study investigated the role of autophagy on human retinal pigment epithelial (RPE) cell viability and apoptosis under oxidative stress. RPE cells were divided into control, H2O2, and H2O2+3-MA groups. H2O2 treatment activated autophagy and increased apoptosis while decreasing cell viability. Inhibition of autophagy with 3-MA decreased apoptosis. The results suggest that autophagy is involved in H2O2-induced apoptosis of RPE cells under oxidative stress conditions.

1. 139
OBJECTIVE: To investigate the role of autophagy on the
cell viability and apoptosis of human retinal pigment epi-
thelial cells (RPE-19) in the condition of oxidative stress.
STUDY DESIGN: RPE-19 cells were divided into 3
groups: control, H2O2 (with H2O2 concentration of 150
μM, cultured 12 hours), and H2O2+3-MA (10 mM of
autophagy inhibitor 3-methyladenine pretreatment for
12 hours, then adding 150 μM H2O2 and cultured 12
hours). After 12 hours the cell autophagy-related pro­
tein LC3 (LC3-II/I ratio), Beclin-1, and p62 were tested
by western blotting, cell vitality was tested by MTT,
and apoptosis was tested by TUNEL assay and western
blotting.
RESULTS: Compared with the control group, the expres-
sion of Beclin-1 and LC3 (LC3-II/I ratio) increased, and
the level of p62 decreased in the H2O2 group. Compared
with the control group, the vitality of RPE-19 cells was
decreased, and the apoptosis was increased in the H2O2
group (p<0.05). Compared with the H2O2 group, the
expression of Beclin-1 and LC3 (LC3-II/I ratio) were
decreased in the H2O2+3-MA group, while the expres-
sion of p62 was increased, RPE-19 cell vitality was
increased, and cell apoptosis was decreased (p<0.05).
CONCLUSION: H2O2 induced the activation of RPE-
19 cell autophagy, the decrease of cell vitality, and the
increase of cell apoptosis. Inhibition of autophagy can
lead to the decrease of cell apoptosis. Autophagy may be
involved in the apoptosis of RPE cells in the condition of
oxidative stress. (Anal Quant Cytopathol Histpathol
2019;41:139–145)
Analytical and Quantitative Cytopathology and Histopathology®
0884-6812/19/4104-0139/$18.00/0 © Science Printers and Publishers, Inc.
Analytical and Quantitative Cytopathology and Histopathology®
Autophagy Is Involved in the Apoptosis of
Human Retinal Pigment Epithelial Cells
Induced by Hydrogen Peroxide
Bobo Yuan, M.S., Zulipiya, B.S., Mengyang Kang, B.S., Rong Li, M.D.,
Tianzhi Cai, M.S., Lina Wang, M.S., Wei Ju, M.S., Kai Lei, M.S.,
Bin Du, M.S., and Junhui Du, M.D.
From the Departments of Neurology and of Ophthalmology, Xi’an Ninth Hospital Affiliated to Medical College of Xi’an Jiaotong Uni-
versity, Xi’an, Shaanxi Province; the Department of Ophthalmology, Urumqi Adiya Eye Hospital, Urumqi, Xinjiang; the Department
of Clinical Medicine, Xi’an Medical University, Weiyang District, Xi’an, Shaanxi Province; the Department of Ophthalmology, the First
Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi Province, China; and the Center for Translational Medicine, Xi’an Ninth
Hospital Affiliated to Medical College of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China.
Drs. Yuan and Wang are Neurologists, Department of Neurology, Xi’an Ninth Hospital Affiliated to Medical College of Xi’an Jiaotong
University.
Dr. Zulipiya is Ophthalmologist, Department of Ophthalmology, Urumqi Adiya Eye Hospital.
Mengyang Kang is Medical Undergraduate Student, Department of Clinical Medicine, Xi’an Medical University.
Drs. Li and Cai are Ophthalmologists, Department of Ophthalmology, the First Affiliated Hospital of Xi’an Medical University.
Drs. Ju, Lei, and B. Du are Medical Researchers, Center for Translational Medicine, Xi’an Ninth Hospital Affiliated to Medical College
of Xi’an Jiaotong University.
Dr. J. Du is Ophthalmologist, Department of Ophthalmology, Xi’an Ninth Hospital Affiliated to Medical College of Xi’an Jiaotong Uni-
versity.
Drs. Yuan and Zulipiya are co-first authors.
This work was supported by grants from the Fundamental Research Funds for the Central Universities (No. 1191329116) and the Natural
Science Foundation of Shaanxi province (No. 2016JM8018).
Address correspondence to: Junhui Du, M.D., Department of Ophthalmology, Xi’an Ninth Hospital Affiliated to Medical College of
Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China (djh79918@163.com).
Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.

2. Keywords: autophagy; hydrogen peroxide; macu-
lar degeneration; oxidative stress; retinal pigment
epithelial cells.
Age-related macular degeneration (AMD) is a com-
mon eye disease that causes vision loss.1,2 The in-
jury and apoptosis of the retinal pigment epithe-
lial cells (RPEs) are the important reasons for the
formation of AMD.3,4 RPE cells can be damaged
by inflammation, oxidative damage, light damage,
etc. In recent years, researchers have found that
autophagy dysfunction is related to RPE cell in-
jury and apoptosis, which play an important role
in the onset of AMD.5-8 Autophagy is the main
approach to remove damaged proteins and organ-
elles in cells, which is essential to maintain ho-
meostasis in cells. The role of autophagy in dam-
age to RPE cells caused by oxidative stress is still
unclear. Therefore, the main purpose of this study
was to confirm the changes of autophagy in RPE
cells and the relationship between autophagy and
cell apoptosis under the condition of oxidative
stress.
Materials and Methods
Cell Culture
The RPE-19 cells were cultivated as previously
described.9 Cells were divided into 3 groups: con-
trol group (cultured 12 hours in fresh culture me-
dium), hydrogen peroxide (H2O2) treatment group
(adding H2O2 in culture, bring the concentration
to 150 μM, cultured 12 hours), and H2O2+3-MA
group (to inhibit autophagy, pretreated the cells
with 3-methyladenine [Sigma, St. Louis, Missouri,
USA; final concentration, 10 mmol/L] for 12 hours,
then adding H2O2 and bringing the concentration
to 150 μM, cultured 12 hours). After 24 hours,
western blotting was used to detect Beclin-1 (Santa
Cruz Biotechnology, USA), LC3B (Santa Cruz Bio-
technology), and p62 (Santa Cruz Biotechnology).
The cell vitality was detected using an MTT assay
(BD Biosciences). The TUNEL method was used to
detect cell apoptosis. All tests were performed in
triplicate.
Western Blotting
The experiment was completed in strict accor-
dance with the reagent instructions. The primary
antibodies of LC3, Beclin-1, and p62 dilution ratios
were 1:500. After cultivation with the horseradish
peroxidase–conjugated secondary antibody at room
temperature for 1 hour, the bands were visualized
with the enhanced chemiluminescence (GE Health-
care Life Sciences, USA), and the labeled bands
were quantified (Clinx, Shanghai, China).
Cell Vitality Assay
The vitality of RPE-19 cells was determined using
MTT assay as previously described.10 RPE-19 cells
were divided into 3 groups as described earlier.
Then, these cells were cultivated at 37°C for 24
hours in 5% CO2 environment, followed by replen-
ishing 20 μL of the 5 g/L MTT in each well, and
cultivated for 4 hours. The medium was discarded.
DMSO 150 μL was added into each well, and the
plates were gently shaken for 10 minutes on an
orbital shaker. Then, we recorded the optical den­
sity at 490 nm on a microplate reader.
TUNEL Assay
The slices were permeabilized with Triton X-100
for 5 minutes at room temperature and washed
with phosphate-buffered saline (PBS) 3 times. These
slices were incubated in 3% H2O2 for 10 minutes at
room temperature and washed with PBS 3 times.
As a positive control, slices were processed with
DNase I for 10 minutes at room temperature and
washed with PBS 3 times. Each positive slice was
marked with 50 μL TdT reaction mixture and cul-
tivated at 37°C for 1 hour in the dark and washed
with PBS 3 times. Then every slice was marked
with 50 μL streptavidin–fluorescein isothiocyanate
mix and cultivated at 37°C for 30 minutes in the
dark and washed with PBS 3 times. A fluorescence
microscope (H600L) captured images which were
excited and emitted at 450 and 515 nm, respectively.
Statistical Analysis
SPSS version 17.0 was applied to all statistical
analyses. All data were expressed as the means±
SEM. Analysis of variance tested between-group
differences (ANOVA). The Student-Newman-Keuls
(SNK) method was used to conduct comparisons
among different pairs of groups. Differences with
p value <0.05 were deemed to be statistically sig-
nificant.
Results
RPE-19 Cell Morphology Under the Inverted Phase
Contrast Microscope
After 12 hours, 3 groups of cell morphology were
observed under inverted phase contrast micro-
scope. The morphology of cells in the control group
was regular and polygonal. After H2O2 treatment,
140 Analytical and Quantitative Cytopathology and Histopathology®
Yuan et al

3. the cell boundary was not clear, the cytoplasm was
shriveled, and the vacuolar structure appeared. Cell
viability was decreased. In the H2O2+3-MA group
the cell morphology was restored to some extent
(Figure 1).
Oxidative Stress Promoted Autophagy in RPE-19 Cells
As shown in Figure 2, the obviously increased lev-
els of Beclin-1 and LC3-II/I were observed in the
RPE-19 cells treated with H2O2; however, 3-MA
significantly decreased the expression levels of
these proteins in the RPE-19 cells. The expression
level of p62 was remarkably reduced in the H2O2
group, and yet it was enhanced when the RPE-19
cells were pretreated with 3-MA. These findings
indicated that H2O2 could activate RPE-19 cell
autophagy, yet 3-MA restrained the autophagy
induced by H2O2 in the RPE-19 cells.
Effects of Inhibition of Autophagy on Cell Viability
Our results revealed that H2O2 can restrain the
cell viability of RPE-19 cells. In the H2O2+3-MA
group the cell activity increased to a certain ex-
tent, but the difference with the H2O2 group was
not statistically significant (Figure 3).
Effects of Inhibition of Autophagy on Apoptosis of
RPE-19
The TUNEL assay indicated that the level of apop­
tosis was significantly higher in the RPE-19 cells
treated with the H2O2 group than in the control
group, and yet the level of apoptosis was de-
creased in the H2O2+3-MA group (Figure 4). As
shown in Figure 5, apoptosis-related proteins
caspase-3 and Bax were remarkably enhanced, and
Bcl-2 was reduced in the H2O2 group. However,
the expression level of caspase-3 and Bax were
decreased in the H2O2+3-MA group, and Bcl-2
was increased in the H2O2+3-MA group. These
results indicate that H2O2 can promote RPE-19 cell
apoptosis, while 3-MA restrained cell apoptosis
induced by H2O2. These results indicate that au-
tophagy may be involved in the process of RPE-19
cell apoptosis in oxidative stress.
Discussion
Oxidative damage has been identified as one of
the causes of AMD. In order to study the role of
autophagy in AMD, we used H2O2 to treat RPE
cells. Our results showed that H2O2 can decrease
RPE-19 cell activity, increase apoptosis, and acti-
vate cell autophagy as well. When we restrained
autophagy, the cell apoptosis was decreased. These
results indicated that autophagy is involved in the
apoptosis of RPE cells induced by H2O2.
Oxidative damage is one of the key factors in
the development of AMD. Oxidative damage can
result in impaired retinal function. Studies found
that many factors are closely related to oxidative
stress which can cause AMD, such as sunlight
exposure, diet, smoking, and vitamin D deficien-
cy.11-13 Normal RPE cells and photoreceptors have
a high demand for oxygen. When the density of
RPE cells decreases, it will eventually lead to the
dysfunction of RPE cells’ metabolism and increase
the content of reactive oxygen species.14 Under
normal circumstances the damage and repair pro-
ceed synchronously after DNA damage, but if
there is excessive reactive oxygen species in RPE
cells and it is more than the antioxidant system’s
ability to remove it, this can cause abnormal DNA
oxidative damage.15,16 The study by Terluk et al
confirmed that oxygenation has a damaging effect
on DNA, which further promotes AMD develop-
ment.17
In recent years, the role of autophagy in RPE
cell damage and AMD has been taken seriously.
Autophagy is a key self-protection mechanism
for maintaining normal function and homeostasis
of the cell.18 Autophagy can be activated under
stress conditions such as nutrient deficiency, oxi­
dative stress, hypoxia, endoplasmic reticulum
Volume 41, Number 4/August 2019 141
Autophagy Promotes H2O2-Induced Apoptosis
Figure 1
Cell morphology of RPE-19
cells in different groups.

4. stress, etc.19 Autophagy plays an important role in
maintaining cellular homeostasis, and it may be a
protective factor for cells.20
However, there is a complex relationship be-
tween autophagy and apoptosis. Sometimes au-
tophagy can protect cells by stabilizing the in-
tracellular environment and thereby inhibiting
apoptosis. However, sometimes the excessive acti-
vation of autophagy may promote cell apoptosis.
Autophagy is closely related to apoptosis, and the
interaction between them is mainly through mo-
lecular mechanisms such as Atg5, bcl-2 protein,
p53, DAPK, etc.21,22 In this study we found that
oxidative stress results in the activation of RPE
cell autophagy, the decrease of cell activity, and
the increase of apoptosis. Inhibited autophagy can
decrease the RPE cell apoptosis induced by oxi-
dative stress. In recent years, studies have found
that autophagy of RPE cells in AMD patients is
impaired, which may be due to the decrease of
autophagy flux caused by impaired RPE cell lyso-
somal function.8 Other studies have found that in
AMD, autophagy dysfunction can damage RPE
cell function, promote the formation of lipofuscin,
and participate in the accumulation of drusen.7,8
142 Analytical and Quantitative Cytopathology and Histopathology®
Yuan et al
Figure 2
Images and quantifications of
Beclin-1, LC3, and p62 with
or without H2O2 and 3-MA
treatment of the RPE-19 cells.
**p<0.01 vs. control group.
##p<0.01 vs. H2O2 group.
Figure 3 Effects of oxidative stress on RPE-19 cell activity.
**p<0.01 vs. control group.

5. Oxidative stress can induce the production of
reactive oxygen species, which can induce au-
tophagy through different signal pathways and
damage endothelial cells.23 In addition, reactive
oxygen species can also cause mitochondrial dam-
age, release proapoptotic proteins, activate caspase
family proteins, and initiate the process of cell
apoptosis, thus causing cell death.24 Autophagy
Volume 41, Number 4/August 2019 143
Autophagy Promotes H2O2-Induced Apoptosis
Figure 4
Detection of cell apoptosis
of the 3 groups by the TUNEL
method. (A) The images of
cell apoptosis. (B) The
quantifications of cell
apoptosis. **p<0.01 vs. control
group. ##p<0.01 vs. H2O2
group.
Figure 5
Images and quantifications of
caspase-3, caspase-8, Bcl-2,
and Bax with or without H2O2
and 3-MA treatment of RPE-19
cells. *p<0.05 vs. control
group. #p<0.05 vs. H2O2
group. ##p<0.01 vs. H2O2
group.

6. and apoptosis can interact and influence each
other. There is a complex relationship between
autophagy and apoptosis, and there are 3 possi-
ble relationships25: (1) Autophagy cooperates with
apoptosis. They work together to complete the cell
death process. (2) Autophagy antagonizes apopto-
sis. Autophagy can keep cells alive by regulating
apoptotic proteins. (3) Autophagy promotes apop-
tosis. Autophagy induces apoptosis by maintain-
ing necessary ATP levels in cells. Autophagy and
apoptosis have some common regulating factors,
such as beclin-1 and bcl-2 families, which are the
intersection of autophagy and apoptosis pathways.
Beclin-1 is an autophagy gene of mammals and
interacts with apoptotic protein bcl-2 and other
proteins.26,27
Oxidative stress can activate autophagy and in-
duce apoptosis; however, the effect of autophagy
on apoptosis is different in different cells or in
different conditions. In our study we found that
the activation of autophagy was involved in the
process of H2O2-induced RPE cell apoptosis. When
autophagy was inhibited, the cell survival rate in-
creased and apoptosis decreased. Apoptosis and
autophagy may antagonize each other or may
occur successively or simultaneously in the pro­
cess of cell death.28 In this study, autophagy acti-
vation is shown to promote apoptosis. Autophagy
may be involved in the apoptosis process through
the following ways. Fas-associated phosphatase-1
(FAP-1) is a negative regulator of Fas metastasis;
knockout of FAP-1 can promote the expression
of Fas on the cell surface. Fas is an important fac-
tor in inducing cell death. FAP-1 can cut off the
transport of Fas from golgi to the cell surface or
reduce the role of cell surface receptors by in-
creasing the transport of Fas from the cell surface
to the cytoplasm. Therefore, FAP-1 plays an im-
portant role in triggering Fas-mediated apoptosis.
Autophagy-induced degradation of FAP-1 makes
cells susceptible to Fas-induced apoptosis.29 More-
over, p53 also plays an important role in the
regulation of autophagy and apoptosis: p53 in
the nucleus can activate AMPK, thus inhibiting
mTOR, and activate autophagy damage adjust-
ment factor (DRAM), thus inducing autophagy,
again through the role of DRAM command cell
under the genotoxic stress response to apopto-
sis.30,31 However, in different cell types, autophagy
has different effects on apoptosis, sometimes pro-
moting apoptosis, sometimes inhibiting apoptosis.32
Therefore, the mechanism of autophagy in RPE
cells and in AMD patients needs to be studied
further. The shortcoming of our study is that we
did not research the mechanism of autophagy and
apoptosis induced by oxidative stress. In addition,
our research results need to be further confirmed
in vivo.
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