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

Abstract

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.

Construction of an Antithrombotic and Anti‐Inflammatory Polyethersulfone Membrane

“…and Gurubaran et al. [ 53,54 ] recently found that thrombin was involved in the enhancement of the terminal pathway producing C5a, independent of C3 activation. Thus, relative to the C3a level, the C5a level may better reflect dialysis membrane inflammation.…”

“…Zuo et al [52] reported that C3a and C5a caused neutrophil chemotaxis, enabling large numbers of neutrophils to aggregate, activate, and release inflammatory factors such as CRP, IL-6, and IL-1𝛽. However, Huber-Lang et al and Gurubaran et al [53,54] recently found that thrombin was involved in the enhancement of the terminal pathway producing C5a, independent of C3 activation. Thus, relative to the C3a level, the C5a level may better reflect dialysis membrane inflammation.…”

PGC‐1α regulates the interplay between oxidative stress, senescence and autophagy in the ageing retina important in age‐related macular degeneration

“…Therefore, the expression of NFE2L2 and PPARGC1A genes may play a role in AMD pathogenesis. In a subsequent work we showed that NFE2L2/PPARGC1A dKO mice showed some alterations in inflammatory pathways that are important in AMD pathogenesis 3 . We also showed that the dKO mice displayed an alternated expression of epithelial‐mesenchymal transition (EMT) transcription factors 4 .…”

“…Effective treatment of AMD is impeded by a poor knowledge of the disease pathogenesis, which is, at least in part, underlined by a restricted accessibility of the human retina for research and limited adequacy of cellular and animal models to mimic human AMD. We established an animal AMD model with mice carrying mutations in the nuclear factor erythroid 2 like 2 ( NFE2L2 ) and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha ( PPARGC1A ) genes (dKO mice), whose phenotype resembled dry AMD 3 . These transgenic animals showed a significant age‐dependent RPE degeneration, an increase in the oxidative stress and endoplasmic reticulum markers, 4‐HNE (4‐hydroxynonenal) and GRP78 (glucose‐regulated protein 78) and damaged mitochondria.…”

Toll-Like Receptor Signalling Pathways and the Pathogenesis of Retinal Diseases

“…Nuclear factor erythroid 2-related factor 2 and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (NFE2L2/PGC1a) are usually involved in the regulation of antioxidant production. Deficiency of this complex was shown to increase the accumulation of drusen-like extracellular material in sub-RPE region (102) with a significant increase noted in TLR3/TLR9 levels in mice retina (102). This was also associated with the increased levels of complement component C5a (102).…”