Oxidative Stress Affects the Junctional Integrity of Retinal Pigment Epithelial Cells

Bailey, Tracey A.; Kanuga, Naheed; Romero, Ignacio A.; Greenwood, John; Luthert, Philip J.; Cheetham, Michael E.

doi:10.1167/iovs.03-0351

Cited by 215 publications

(175 citation statements)

References 29 publications

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“…It should be noted that the highly differentiated RPE cells (Fig. 6B) are more resistant to TBHP oxidative damage, consistent with what has been reported previously (32).…”

Section: Sulindac Protection Of Rpe Cells Involves Both Mitochondrialsupporting

confidence: 91%

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

Sur

Kesaraju

Prentice

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The retinal pigmented epithelial (RPE) layer is one of the major ocular tissues affected by oxidative stress and is known to play an important role in the etiology of age-related macular degeneration (AMD), the major cause of blinding in the elderly. In the present study, sulindac, a nonsteroidal antiinflammatory drug (NSAID), was tested for protection against oxidative stressinduced damage in an established RPE cell line . Besides its established antiinflammatory activity, sulindac has previously been shown to protect cardiac tissue against ischemia/reperfusion damage, although the exact mechanism was not elucidated. As shown here, sulindac can also protect RPE cells from chemical oxidative damage or UV light by initiating a protective mechanism similar to what is observed in ischemic preconditioning (IPC) response. The mechanism of protection appears to be triggered by reactive oxygen species (ROS) and involves known IPC signaling components such as PKG and PKC epsilon in addition to the mitochondrial ATP-sensitive K + channel. Sulindac induced iNOS and Hsp70, late-phase IPC markers in the RPE cells. A unique feature of the sulindac protective response is that it involves activation of the peroxisome proliferator-activated receptor alpha (PPAR-α). We have also used low-passage human fetal RPE and polarized primary fetal RPE cells to validate the basic observation that sulindac can protect retinal cells against oxidative stress. These findings indicate a mechanism for preventing oxidative stress in RPE cells and suggest that sulindac could be used therapeutically for slowing the progression of AMD.preconditioning | oxidative stress | sulindac | retinal pigmented epithelial cells | age-related macular degeneration O xidative damage, resulting from excess production of reactive oxygen species (ROS), has been implicated in the progression of key ocular disorders such as cataracts, glaucoma, and age-related macular degeneration (AMD). Death of retinal pigmented epithelial (RPE) cells has been shown to be an important contributor to AMD pathophysiology. RPE cells are known to be highly metabolically active, and there is strong evidence that the RPE cells are sensitive to oxidative stress (1). It has been reported that the pathophysiology of AMD is due to cumulative oxidative damage to RPE cells resulting from an imbalance between the generation of ROS and the ability of these cells to destroy and/or protect against ROS damage to macromolecules (2, 3). Hence, strategies for protecting RPE cells against oxidative damage may be particularly important in maintaining retinal function and preventing the development or progression of AMD.Sulindac was one of the first nonsteroidal antiinflammatory drugs (NSAIDs) used to treat inflammation. It is a prodrug, composed of R and S epimers, whose NSAID activity is dependent on the reduction of the epimers to sulindac sulfide, the active cyclooxygenase (COX) inhibitor (4). This reduction is catalyzed by two members of the methionine sulfoxide reductase (Msr) family, MsrA and MsrB,...

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“…It should be noted that the highly differentiated RPE cells (Fig. 6B) are more resistant to TBHP oxidative damage, consistent with what has been reported previously (32).…”

Section: Sulindac Protection Of Rpe Cells Involves Both Mitochondrialsupporting

confidence: 91%

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

Sur

Kesaraju

Prentice

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Accordingly, PG-mediated regulation of phagocytotic activity may be involved in the mechanism of Trx-and GGA-mediated protection of phagocytotic activity against oxidative stress. Because the levels of Hsp72 contribute to the increased resistance to H 2 O 2 -mediated cell damage in cultured RPE cells (Bailey et al, 2004), and because Hsp72 is stimulated in macrophages that are actively engaged in phagocytosis (Kantengwa and Polla, 1993), Hsp72 induced in the RPE may be involved in GGA-mediated protection of phagocytotic activity against oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Cytoprotective Effects of Geranylgeranylacetone against Retinal Photooxidative Damage

Tanito¹,

Kwon²,

Kondo³

et al. 2005

J. Neurosci.

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Exposure to excessive light induces retinal photoreceptor cell damage, leading to development and progression of various retinal diseases. We tested the effect of geranylgeranylacetone (GGA), an acyclic polyisoprenoid, on light-induced retinal damage in mice. Oral treatment with GGA (1.0 mg/d) for 5 d induced thioredoxin (Trx) and heat shock protein 72 (Hsp72) predominantly in the retinal pigment epithelium (RPE). After white light exposure (8000 lux for 2 h), the percentage of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive photoreceptor cells decreased significantly at 24 and 96 h, and the number of photoreceptor cell nuclei at 96 h and the electroretinographic amplitudes of the a- and b-waves at 4 and 10 d increased significantly in GGA-pretreated mice compared with saline-pretreated mice. Light-induced upregulations of 8-hydroxy-2-deoxyguanosine and 4-hydroxy-2-nonenal-modified protein, markers of oxidative stress, were inhibited by GGA pretreatment. To elucidate the cytoprotective mechanism of GGA and Trx, we used human K-1034 RPE cells and mouse photoreceptor-derived 661W cells. In K-1034 cells, GGA (10 μm) induced intracellular Trx, Hsp72, and extracellular Trx but not extracellular Hsp72. Extracellular Trx (0.75 nm) attenuated H2O2(200 μm)-induced cell damage in 661W cells. Pretreatment with GGA and overexpression of Trx in K-1034 cells counteracted H2O2(50 μm)-induced attenuation of cellular latex bead incorporation. Protection of phagocytotic activity through induction of Trx and possibly Hsp72 in RPE cells and elimination of oxidative stress in the photoreceptor layer through release of Trx from RPE cells may be mechanisms of GGA-mediated cytoprotection. Therefore, Trx is a neurotrophic factor released from RPE cells and plays a crucial role in maintaining photoreceptor cell integrity.

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“…It has previously been reported that doses of up to 1 mM are not cytotoxic, and do not lead to disruption of barrier function in these cells (19). After treatment with H 2 O 2 , monolayers were immediately exposed to 25% NHS as a source of complement proteins (18).…”

Section: Methodsmentioning

confidence: 99%

“…These monolayers exhibit stable transepithelial resistance of ϳ40 -45 ohm/ cm 2 ; are polarized; and stain for markers of tight and adherence junctions (19). In addition, the Cheetham group has shown that ARPE-19 cells when grown as monolayers, are resistant to oxidative damage; while subconfluent ARPE-19 cells exposed to oxidative stress (Ն0.1 mM H 2 O 2 ) undergo apoptosis (20), those grown in monolayers show no sign of damage up to 0.5 mM (19). The earliest sign of damage occurs with H 2 O 2 concentrations above 1 mM, resulting in a reduction of transepithelial resistance (TER) (19).…”

mentioning

confidence: 99%

“…In addition, the Cheetham group has shown that ARPE-19 cells when grown as monolayers, are resistant to oxidative damage; while subconfluent ARPE-19 cells exposed to oxidative stress (Ն0.1 mM H 2 O 2 ) undergo apoptosis (20), those grown in monolayers show no sign of damage up to 0.5 mM (19). The earliest sign of damage occurs with H 2 O 2 concentrations above 1 mM, resulting in a reduction of transepithelial resistance (TER) (19). Thus, we asked whether a concentration that did not affect the epithelial integrity (0.1 mM H 2 O 2 ), sensitized the cells to complement attack.…”

mentioning

confidence: 99%

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Sublytic Membrane-Attack-Complex (MAC) Activation Alters Regulated Rather than Constitutive Vascular Endothelial Growth Factor (VEGF) Secretion in Retinal Pigment Epithelium Monolayers

Kunchithapautham

Rohrer

2011

Journal of Biological Chemistry

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Uncontrolled activation of the alternative complement pathway and secretion of vascular endothelial growth factor (VEGF) are thought to be associated with age-related macular degeneration (AMD). Previously, we have shown that in RPE monolayers, oxidative-stress reduced complement inhibition on the cell surface. The resulting increased level of sublytic complement activation resulted in VEGF release, which disrupted the barrier facility of these cells as determined by transepithelial resistance (TER) measurements. Induced rather than basal VEGF release in RPE is thought to be controlled by different mechanisms, including voltage-dependent calcium channel (VDCC) activation and mitogenactivated protein kinases. Here we examined the potential intracellular links between sublytic complement activation and VEGF release in RPE cells challenged with H 2 O 2 and complement-sufficient normal human serum (NHS). Disruption of barrier function by H 2 O 2 ؉ NHS rapidly increased Ras expression and Erk and Src phosphorylation, but had no effect on P38 phosphorylation. Either treatment alone had little effect. TER reduction could be attenuated by inhibiting Ras, Erk and Src activation, or blocking VDCC or VEGF-R2 activation, but not by inhibiting P38. Combinatorial analysis of inhibitor effects demonstrated that sublytic complement activation triggers VEGF secretion via two pathways, Src and Ras-Erk, with the latter being amplified by VEGF-R2 activation, but has no effect on constitutive VEGF secretion mediated via P38. Finally, effects on TER were directly correlated with release of VEGF; and sublytic MAC activation decreased levels of zfp36, a negative modulator of VEGF transcription, resulting in increased VEGF expression. Taken together, identifying how sublytic MAC induces VEGF expression and secretion might offer opportunities to selectively inhibit pathological VEGF release only.

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Oxidative Stress Affects the Junctional Integrity of Retinal Pigment Epithelial Cells

Cited by 215 publications

References 29 publications

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

Cytoprotective Effects of Geranylgeranylacetone against Retinal Photooxidative Damage

Sublytic Membrane-Attack-Complex (MAC) Activation Alters Regulated Rather than Constitutive Vascular Endothelial Growth Factor (VEGF) Secretion in Retinal Pigment Epithelium Monolayers

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