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