Chapter Four - Mechanisms for Countering Oxidative Stress and Damage in Retinal Pigment Epithelium

https://doi.org/10.1016/B978-0-12-394309-5.00004-3Get rights and content

Abstract

Clinical and experimental evidence supports that chronic oxidative stress is a primary contributing factor to numerous retinal degenerative diseases, such as age-related macular degeneration (AMD). Eyes obtained postmortem from AMD patients have extensive free radical damage to the proteins, lipids, DNA, and mitochondria of their retinal pigment epithelial (RPE) cells. In addition, several mouse models of chronic oxidative stress develop many of the pathological hallmarks of AMD. However, the extent to which oxidative stress is an etiologic component versus its involvement in disease progression remains a major unanswered question. Further, whether the primary target of oxidative stress and damage is photoreceptors or RPE cells, or both, is still unclear. In this review, we discuss the major functions of RPE cells with an emphasis on the oxidative challenges these cells encounter and the endogenous antioxidant mechanisms employed to neutralize the deleterious effects that such stresses can elicit if left unchecked.

Introduction

The retinal pigment epithelium (RPE) is a single layer of epithelial cells lining the posterior segment of the eye. It is located between the light-sensing photoreceptor cells and the choriocapillaris. Similar to other epithelial cell types, RPE cells are polarized. The apical processes are interdigitated with the outer segments of the photoreceptors, whereas the basolateral side of each cell is aligned along a specialized membrane called Bruch's membrane (BM) underlying the fenestrated endothelium of the choriocapillaris.

The anatomical positioning of the RPE layer situates these cells for their numerous support functions as guardian and caretaker of the photoreceptors (Strauss, 2005). In conjunction with the endothelium of the retinal vessels, the RPE layer forms the blood–retinal barrier. A primary function of this barrier is to mediate the uptake of ions, water, and nutrients while simultaneously removing metabolic waste products from the subretinal space. These exchange processes are central for maintaining overall metabolic homeostasis and sustenance of the photoreceptor cells. A complementary function of the RPE involves retinoid storage and metabolism. In the classical visual cycle associated with rod photoreceptors, RPE cells convert all-trans-retinol (vitamin A) into 11-cis-retinal and then deliver the 11-cis-retinal to the photoreceptors for phototransduction. 11-cis-Retinal is a chromophoric derivative of vitamin A that binds opsin to generate rhodopsin in photoreceptor outer segments. Coincident with the absorption of a photon of light by rhodopsin and initiation of the phototransduction cascade, 11-cis-retinal is photoisomerized into all-trans-retinal. Upon release from opsin, the all-trans-retinal is reduced in the cytoplasm to all-trans-retinol by all-trans retinol dehydrogenase and subsequently exported to the RPE for recycling back into 11-cis-retinal. The regeneration of 11-cis-retinal in the RPE occurs via an enzymatic cascade consisting of lecithin retinol acyltransferase, RPE65, and 11-cis retinol dehydrogenase. Vitamin A from the circulation also enters RPE cells from the basal side and is likewise processed by these enzymes to produce 11-cis-retinal.

RPE cells are enriched in numerous pigments, such as melanin, lipofuscin, and flavins, which absorb excess light and thereby function to protect the neuroretina from phototoxicity. Paradoxically, these same moieties can underlie photochemical damage to the RPE and retina (Boulton et al., 2001). An additional key function performed by RPE cells is the maintenance of photoreceptor outer segment length. Each day, the RPE ingests the distal tips of the outer segments and, in doing so, balances the growth of these segments that occurs at the proximal end where new membrane stacks are generated. This trimming function of the RPE ensures that a relatively constant outer segment length is maintained, which is essential for proper photoreceptor function (Bok and Hall, 1971, Edwards and Szamier, 1977, LaVail, 1983, Nandrot et al., 2004). RPE cells also secrete growth factors in a directional fashion. Most notably, they release vascular endothelial growth factor basolaterally to the choriocapillaris and pigment epithelial-derived growth factor apically to the subretinal space. Additional immunosuppressive factors are also produced and released by RPE cells to impart immune privilege to ocular tissues (Ishida et al., 2003).

Section snippets

Sources of oxidative stress in RPE

The panoply of functions carried out by RPE highlights its central role as guardian and caretaker of the neural retina. It is no coincidence then that impairment of one or more of the above RPE processes can have dire consequences for ocular health and vision. A growing body of clinical and experimental data strongly implicate oxidative stress, and, in particular, chronic intracellular oxidative stress, as a constant threat to the structural and functional integrity of the RPE.

The sources of

Preservation of RPE Integrity and Function

In light of the challenges that oxidative stress poses to RPE health, function, and survival, it is typically not until the later years of life (i.e., age 60–65) that pathological hallmarks in this cell layer begin to manifest, as in the case of AMD. We speculate that two major mechanisms likely account for this. One is the collective workings of the endogenous antioxidant defense system. The second is RPE regeneration.

Mitochondrial Network Dynamics

As briefly discussed in 2.1 Sources of oxidative stress in RPE, 2.2 Targets of oxidative damage in RPE, mitochondria are both a major source and target of ROS in RPE cells. As such, this section elaborates on the proteins that regulate mitochondrial dynamics with the idea that a comprehensive understanding of these dynamics will potentially facilitate drug development efforts to abrogate RPE atrophy. Mitochondria have historically been depicted as individual, round organelles that act

Overview of the UPS system

Intracellular proteins that become damaged and/or misfolded by oxidative stress are typically destined for one of three fates. They can be repaired and refolded, sequestered in aggregates, or targeted for degradation. The UPS plays a major role in targeting and degrading such damaged proteins. The central player of this system is Ub, a highly conserved, 76-amino acid polypeptide that is posttranslationally attached to lysine residues on target proteins. The conjugation of Ub to a target protein

Concluding Remarks

Based on the functions of RPE cells and their susceptibility to chronic oxidative challenge, we posit the following model for the events that trigger RPE atrophy in maculopathies such as AMD (Fig. 4.2). As we age, A2E and related bisretinoids compromise the capacity of the RPE lysosomal system to efficiently and completely degrade the phospholipids of ingested photoreceptor outer segments (Finnemann et al., 2002). This leads to bisretinoid accumulation as outer segments are continually

Acknowledgments

Work in the Plafker laboratory is supported in part by grant 1R01GM092900-A1 from NIH/NIGMS, by a Karl Kirchgessner Foundation Vision Research Grant, and by monies from the Oklahoma Medical Research Foundation (OMRF). We apologize to any colleagues whose work was inadvertently overlooked or not cited.

References (225)

  • Y. David et al.

    E3 ligases determine ubiquitination site and conjugate type by enforcing specificity on E2 enzymes

    J. Biol. Chem.

    (2011)
  • L.F. Dmitriev et al.

    Lipid peroxidation in relation to ageing and the role of endogenous aldehydes in diabetes and other age-related diseases

    Ageing Res. Rev.

    (2010)
  • J. Esteve-Rudd et al.

    Expression in the mammalian retina of parkin and UCH-L1, two components of the ubiquitin-proteasome system

    Brain Res.

    (2010)
  • J. Feher et al.

    Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration

    Neurobiol. Aging

    (2006)
  • R.N. Frank et al.

    Antioxidant enzymes in the macular retinal pigment epithelium of eyes with neovascular age-related macular degeneration

    Am. J. Ophthalmol.

    (1999)
  • J.S. Friedman et al.

    Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa

    Am. J. Hum. Genet.

    (2009)
  • O. Guillery et al.

    Modulation of mitochondrial morphology by bioenergetics defects in primary human fibroblasts

    Neuromuscul. Disord.

    (2008)
  • V.K. Gullapalli et al.

    Impaired RPE survival on aged submacular human Bruch's membrane

    Exp. Eye Res.

    (2005)
  • A.L. Haas et al.

    The mechanism of ubiquitin activating enzyme. A kinetic and equilibrium analysis

    J. Biol. Chem.

    (1982)
  • A.L. Haas et al.

    Ubiquitin-activating enzyme. Mechanism and role in protein-ubiquitin conjugation

    J. Biol. Chem.

    (1982)
  • J. Hanna et al.

    Deubiquitinating enzyme Ubp6 functions noncatalytically to delay proteasomal degradation

    Cell

    (2006)
  • S. Hoppins et al.

    The soluble form of Bax regulates mitochondrial fusion via MFN2 homotypic complexes

    Mol. Cell

    (2011)
  • J. Jahngen-Hodge et al.

    Regulation of ubiquitin-conjugating enzymes by glutathione following oxidative stress

    J. Biol. Chem.

    (1997)
  • D.I. James et al.

    hFis1, a novel component of the mammalian mitochondrial fission machinery

    J. Biol. Chem.

    (2003)
  • K. Kalishwaralal et al.

    Silver nanoparticles impede the biofilm formation by Pseudomonas aeruginosa and Staphylococcus epidermidis

    Colloids Surf. B Biointerfaces

    (2010)
  • H.T. Kim et al.

    Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages

    J. Biol. Chem.

    (2007)
  • M.F. Kleijnen et al.

    The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome

    Mol. Cell

    (2000)
  • M.K. Kwak et al.

    Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival

    J. Biol. Chem.

    (2003)
  • V.A. Alder et al.

    The effect of the retinal circulation on vitreal oxygen tension

    Curr. Eye Res.

    (1985)
  • A. Alm et al.

    Blood flow and oxygen extraction in the cat uvea at normal and high intraocular pressures

    Acta Physiol. Scand.

    (1970)
  • A. Alm et al.

    The oxygen supply to the retina. I. Effects of changes in intraocular and arterial blood pressures, and in arterial P O2 and P CO2 on the oxygen tension in the vitreous body of the cat

    Acta Physiol. Scand.

    (1972)
  • A. Alm et al.

    The oxygen supply to the retina. II. Effects of high intraocular pressure and of increased arterial carbon dioxide tension on uveal and retinal blood flow in cats. A study with radioactively labelled microspheres including flow determinations in brain and some other tissues

    Acta Physiol. Scand.

    (1972)
  • N. Ballatori et al.

    Glutathione dysregulation and the etiology and progression of human diseases

    Biol. Chem.

    (2009)
  • E. Bartee et al.

    Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins

    J. Virol.

    (2004)
  • M. Bergmann et al.

    Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute to the pathogenesis of age-related macular degeneration

    FASEB J.

    (2004)
  • D.G. Birch et al.

    Age-related macular degeneration: a target for nanotechnology derived medicines

    Int. J. Nanomedicine

    (2007)
  • D. Bok et al.

    The role of the pigment epithelium in the etiology of inherited retinal dystrophy in the rat

    J. Cell Biol.

    (1971)
  • L. Bonfanti et al.

    Distribution of protein gene product 9.5 (PGP 9.5) in the vertebrate retina: evidence that immunoreactivity is restricted to mammalian horizontal and ganglion cells

    J. Comp. Neurol.

    (1992)
  • A. Borodovsky et al.

    A novel active site-directed probe specific for deubiquitylating enzymes reveals proteasome association of USP14

    EMBO J.

    (2001)
  • D.R. Bosu et al.

    Cullin-RING ubiquitin ligases: global regulation and activation cycles

    Cell Div.

    (2008)
  • E. Braschi et al.

    MAPL is a new mitochondrial SUMO E3 ligase that regulates mitochondrial fission

    EMBO Rep.

    (2009)
  • B.C. Braun et al.

    The base of the proteasome regulatory particle exhibits chaperone-like activity

    Nat. Cell Biol.

    (1999)
  • S. Braun et al.

    Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound

    Mol. Cell. Biol.

    (2002)
  • D. Chan

    Cigarette smoking and age-related macular degeneration

    Optom. Vis. Sci.

    (1998)
  • V. Chau et al.

    A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein

    Science

    (1989)
  • B. Chen et al.

    Cellular strategies of protein quality control

    Cold Spring Harb. Perspect. Biol.

    (2011)
  • D.H. Cho et al.

    S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury

    Science

    (2009)
  • S. Cipolat et al.

    OPA1 requires mitofusin 1 to promote mitochondrial fusion

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

    (2004)
  • A.C. Cohn et al.

    Autosomal dominant optic atrophy: penetrance and expressivity in patients with OPA1 mutations

    Am. J. Ophthalmol.

    (2007)
  • K.J. Cruickshanks et al.

    Sunlight and age-related macular degeneration. The Beaver Dam Eye Study

    Arch. Ophthalmol.

    (1993)
  • Cited by (98)

    • MiR-125b attenuates retinal pigment epithelium oxidative damage via targeting Nrf2/HIF-1α signal pathway

      2022, Experimental Cell Research
      Citation Excerpt :

      Much clinical and experimental evidence has strongly proved that dysregulated oxidative stress poses tremendous threat to the structural and functional integrity of RPE. Therefore, breakthroughs in developing therapies that limit the generation of excessive levels of oxidative stress in this epithelial cell layer are urgently required [32,33]. The transcription factor Nrf2, via binding to the ARE of phase II detoxification enzymes and antioxidant genes, is considered the major protective factor in the cellular antioxidant response [34].

    • Editorial

      2021, Redox Biology
    View all citing articles on Scopus
    View full text