Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3

Aging-associated chronic oxidative stress and inflammation are known to be involved in various diseases, e.g., age-related macular degeneration (AMD). Previously, we reported the presence of dry AMD-like signs, such as elevated oxidative stress, dysfunctional mitophagy and the accumulation of detrimental oxidized materials in the retinal pigment epithelial (RPE) cells of nuclear factor erythroid 2-related factor 2, and a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (NFE2L2/PGC1α) double knockout (dKO) mouse model. Here, we investigated the dynamics of inflammatory markers in one-year-old NFE2L2/PGC1α dKO mice. Immunohistochemical analysis revealed an increase in levels of Toll-like receptors 3 and 9, while those of NOD-like receptor 3 were decreased in NFE2L2/PGC1α dKO retinal specimens as compared to wild type animals. Further analysis showed a trend towards an increase in complement component C5a independent of component C3, observed to be tightly regulated by complement factor H. Interestingly, we found that thrombin, a serine protease enzyme, was involved in enhancing the terminal pathway producing C5a, independent of C3. We also detected an increase in primary acute phase C-reactive protein and receptor for advanced glycation end products in NFE2L2/PGC1α dKO retina. Our main data show C5 and thrombin upregulation together with decreased C3 levels in this dry AMD-like model. In general, the retina strives to mount an orchestrated inflammatory response while attempting to maintain tissue homeostasis and resolve inflammation.

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Age-Related Macular Degeneration: What Do We Know So Far?

Acta medica Lituanica ◽

10.15388/amed.2021.28.1.7 ◽

2021 ◽

Vol 28 (1) ◽

pp. 7

Author(s):

Ho Hin Ma ◽

Rasa Liutkevičienė

Keyword(s):

Visual Impairment ◽

Macular Degeneration ◽

Developed Countries ◽

Factor H ◽

Diagnostic Methods ◽

Age Related Macular Degeneration ◽

Complement Factor ◽

Physiological Changes ◽

Age Related ◽

Dry Amd

Ageing is a natural process that everyone experiences and nobody is an exception. With ageing, our body experiences physiological changes. In this article, the focus is made on the physiological changes of our eyes related to ageing and age-related macular degeneration (AMD), which is the most common cause of incurable visual impairment in developed countries. With ageing populations increasing in many countries, more and more patients will have AMD in a foreseeable future. In Eastern Europe, blindness due to AMD, currently, is approximately 20% and there has been an increasing trend depicted in the future. Generally, AMD can be divided into early stages and two forms in an advanced (late) stage. Advanced AMD form includes neovascular AMD (wet) and geographic atrophy (late dry), both of these are associated with substantial, progressive visual impairment. The pathogenesis of AMD is complex and, by far, not completely understood. Multiple factors have been studied, for example: environmental factor, genetic factor (complement factor H), lifestyle. It has been proved that they are linked to higher the risk of developing of AMD, however, the actual pathogenesis is not yet formulated. AMD progression can also be a culprit to certain biochemical events and molecular changes linked to inflammation and pathological angiogenesis. In nowadays, we do have diagnostic methods for both early and late forms of AMD as well as ways to prevent progression of early AMD and wet AMD. However, until now, there is still no treatment for dry AMD. This article is a brief review of AMD and may hopefully lead to some future directions in early diagnostic methods and treating dry AMD.

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Oxidative stress and mitochondrial damage evoke complement component C5 activation independent of component C3 in dry age‐related macular degeneration like NFE2L2/ PGC‐1α ‐/‐ mouse model

Acta Ophthalmologica ◽

10.1111/j.1755-3768.2022.013 ◽

2022 ◽

Vol 100 (S267) ◽

Author(s):

Iswariyaraja Sridevi Gurubaran ◽

Hanna Heloterä ◽

Stephen Marry ◽

Ali Koskela ◽

Juha M. T. Hyttinen ◽

...

Keyword(s):

Oxidative Stress ◽

Mouse Model ◽

Macular Degeneration ◽

Mitochondrial Damage ◽

Complement Component ◽

Age Related Macular Degeneration ◽

Age Related

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Interlink between Inflammation and Oxidative Stress in Age-Related Macular Degeneration: Role of Complement Factor H

Biomedicines ◽

10.3390/biomedicines9070763 ◽

2021 ◽

Vol 9 (7) ◽

pp. 763

Author(s):

Sara Romero-Vazquez ◽

Víctor Llorens ◽

Alba Soler-Boronat ◽

Marc Figueras-Roca ◽

Alfredo Adan ◽

...

Keyword(s):

Oxidative Stress ◽

Risk Factors ◽

Macular Degeneration ◽

Factor H ◽

Age Related Macular Degeneration ◽

Complement Factor H ◽

Low Grade ◽

Complement Factor ◽

Age Related ◽

And Oxidative Stress

Age-related macular degeneration (AMD) heads the list of legal blindness among the elderly population in developed countries. Due to the complex nature of the retina and the variety of risk factors and mechanisms involved, the molecular pathways underlying AMD are not yet fully defined. Persistent low-grade inflammation and oxidative stress eventually lead to retinal pigment epithelium dysfunction and outer blood–retinal barrier (oBRB) breakdown. The identification of AMD susceptibility genes encoding complement factors, and the presence of inflammatory mediators in drusen, the hallmark deposits of AMD, supports the notion that immune-mediated processes are major drivers of AMD pathobiology. Complement factor H (FH), the main regulator of the alternative pathway of the complement system, may have a key contribution in the pathogenesis of AMD as it is able to regulate both inflammatory and oxidative stress responses in the oBRB. Indeed, genetic variants in the CFH gene account for the strongest genetic risk factors for AMD. In this review, we focus on the roles of inflammation and oxidative stress and their connection with FH and related proteins as regulators of both phenomena in the context of AMD.

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Pinosylvin Extract Retinari™ Sustains Electrophysiological Function, Prevents Thinning of Retina, and Enhances Cellular Response to Oxidative Stress in NFE2L2 Knockout Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8028427 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Toni Tamminen ◽

Ali Koskela ◽

Elisa Toropainen ◽

Iswariyaraja Sridevi Gurubaran ◽

Mateusz Winiarczyk ◽

...

Keyword(s):

Oxidative Stress ◽

Macular Degeneration ◽

Knockout Mice ◽

Disease Model ◽

Factor H ◽

Retinal Function ◽

Age Related Macular Degeneration ◽

Complement Factor ◽

Age Related ◽

Chronic Oxidative Stress

Chronic oxidative stress eventually leads to protein aggregation in combination with impaired autophagy, which has been observed in age-related macular degeneration. We have previously shown an effective age-related macular degeneration disease model in mice with nuclear factor-erythroid 2-related factor-2 (NFE2L2) knockout. We have also shown pinosylvin, a polyphenol abundant in bark waste, to increase human retinal pigment epithelium cell viability in vitro. In this work, the effects of commercial natural pinosylvin extract, Retinari™, were studied on the electroretinogram, optical coherence tomogram, autophagic activity, antioxidant capacity, and inflammation markers. Wild-type and NFE2L2 knockout mice were raised until the age of 14.8 ± 3.8 months. They were fed with either regular or Retinari™ chow ( 141 ± 17.0 mg/kg/day of pinosylvin) for 10 weeks before the assays. Retinari™ treatment preserved significant retinal function with significantly preserved a- and b-wave amplitudes in the electroretinogram responses. Additionally, the treatment prevented thinning of the retina in the NFE2L2 knockout mice. The NFE2L2 knockout mice showed reduced ubiquitin-tagged protein accumulation in addition to local upregulation of complement factor H and antioxidant enzymes superoxide dismutase 1 and catalase. Therefore, the treatment in the NFE2L2 KO disease model led to reduced chronic oxidative stress and sustained retinal function and morphology. Our results demonstrate that pinosylvin supplementation could potentially lower the risk of age-related macular degeneration onset and slow down its progression.

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