Senescent Retinal Pigment Epithelial Cells Are More Sensitive to Vascular Endothelial Growth Factor: Implications for “Wet” Age-Related Macular Degeneration

Kozlowski, Michael R.

doi:10.1089/jop.2014.0071

Cited by 7 publications

(2 citation statements)

References 33 publications

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“…AMD is not strictly localized to the choriocapillaris, RPE or the retina, since many systemic regulators affect its development [27]. As we and others have shown, senescence could be an important factor of AMD pathogenesis [28][29][30]. Moreover, although established mainly in cancer, it is generally accepted that senescence intersects with EMT [31,32].…”

Section: Discussionmentioning

confidence: 99%

Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice

Błasiak

Koskela

Pawłowska

et al. 2021

IJMS

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Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. In our previous studies, we found that deficiencies in the nuclear factor, erythroid 2 like 2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) genes caused AMD-like pathological phenotypes in mice. In the present work, we show hijacked epithelial-mesenchymal transition (EMT) due to the common loss of PGC-1α and NFE2L2 (double knock-out, dKO) genes in aged animals. The implanted area was assessed by histology, immunohistochemistry and transmission electron microscopy. Confocal microscopy revealed altered regions in the filamentous actin ring. This contrasted with hexagonal RPE morphology in wild-type mice. The ultrastructural RPE features here illustrated loss of apical microvilli, alteration of cell-cell contact, loss of basal in-folding with deposits on Bruch’s membrane, and excessive lipofuscin deposition in dKO samples. We also found the expression of epithelial-mesenchymal transition transcription factors, such as Snail, Slug, collagen 1, vimentin and OB-cadherin, to be significantly different in dKO RPEs. An increased immunoreactivity of senescence markers p16, DEC1 and HMGB1 was also noted. These findings suggest that EMT and senescence pathways may intersect in the retinas of dKO mice. Both processes can be activated by damage to the RPE, which may be caused by increased oxidative stress resulting from the absence of NFE2L2 and PGC-1α genes, important for antioxidant defense. This dKO model may provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease.

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Section: Discussionmentioning

confidence: 99%

Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice

Błasiak

Koskela

Pawłowska

et al. 2021

IJMS

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“…This is of therapeutic significance, but the mechanism underlying this effect is not clear. Since telomerase prevents erosion of telomeres and delays the senescence of RPE cells, it may be directly related to AMD pathogenesis [2,67,70,141]. However, as previously mentioned, the absolute length of telomeres might not be causal for cellular states, including senescence [3].…”

Section: Discussionmentioning

confidence: 99%

Potential of Telomerase in Age-Related Macular Degeneration—Involvement of Senescence, DNA Damage Response and Autophagy and a Key Role of PGC-1α

Błasiak

Szczepańska

Fila

et al. 2021

IJMS

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Age-related macular degeneration (AMD), the main cause of vision loss in the elderly, is associated with oxidation in the retina cells promoting telomere attrition. Activation of telomerase was reported to improve macular functions in AMD patients. The catalytic subunit of human telomerase (hTERT) may directly interact with proteins important for senescence, DNA damage response, and autophagy, which are impaired in AMD. hTERT interaction with mTORC1 (mTOR (mechanistic target of rapamycin) complex 1) and PINK1 (PTEN-induced kinase 1) activates macroautophagy and mitophagy, respectively, and removes cellular debris accumulated over AMD progression. Ectopic expression of telomerase in retinal pigment epithelium (RPE) cells lengthened telomeres, reduced senescence, and extended their lifespan. These effects provide evidence for the potential of telomerase in AMD therapy. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may be involved in AMD pathogenesis through decreasing oxidative stress and senescence, regulation of vascular endothelial growth factor (VEGF), and improving autophagy. PGC-1α and TERT form an inhibitory positive feedback loop. In conclusion, telomerase activation and its ectopic expression in RPE cells, as well as controlled clinical trials on the effects of telomerase activation in AMD patients, are justified and should be assisted by PGC-1α modulators to increase the therapeutic potential of telomerase in AMD.

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Senescence in the pathogenesis of age-related macular degeneration

Błasiak

2020

Cell. Mol. Life Sci.

114

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Senescent Retinal Pigment Epithelial Cells Are More Sensitive to Vascular Endothelial Growth Factor: Implications for “Wet” Age-Related Macular Degeneration

Cited by 7 publications

References 33 publications

Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice

Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice

Potential of Telomerase in Age-Related Macular Degeneration—Involvement of Senescence, DNA Damage Response and Autophagy and a Key Role of PGC-1α

Senescence in the pathogenesis of age-related macular degeneration

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