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Article

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

1
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, 70210 Kuopio, Finland
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Department of Ophthalmology, Roche Oy, 02100 Espoo, Finland
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The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Queens University Belfast, Belfast BT9 7BL, UK
4
Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, 70210 Kuopio, Finland
5
Department of Ophthalmology, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland
*
Author to whom correspondence should be addressed.
Academic Editor: Hiroetsu Suzuki
Biology 2021, 10(7), 622; https://doi.org/10.3390/biology10070622
Received: 8 June 2021 / Revised: 30 June 2021 / Accepted: 2 July 2021 / Published: 4 July 2021
(This article belongs to the Special Issue Animal Models for Gene Function and Disease Mechanisms)
Age-related macular degeneration (AMD) is an eye disease that results in permanent loss of vision due to degeneration in the central portion of the retina called the macula. Patients with severe visual loss have reduced quality of life and the risk of death is 2.4 times higher than the general population. Currently, there is no treatment to stop or cure dry AMD. Aging-associated chronic oxidative stress and inflammation are known to be involved in AMD pathology. To investigate the molecular mechanism behind the cause and to develop novel therapy, we have created and validated an animal model mimicking clinical features of dry AMD. Here, we show previously unknown thrombin-mediated complement component C5a activation in the degenerative retina without upregulation of C3. Our model might provide insight into AMD progression and help to develop novel therapies.
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. View Full-Text
Keywords: aging; oxidative stress; mitochondrial damage; age-related macular degeneration; inflammation; complement system; Toll-like receptors; complement factor H; thrombin; C-reactive protein; receptor for advanced glycation end products aging; oxidative stress; mitochondrial damage; age-related macular degeneration; inflammation; complement system; Toll-like receptors; complement factor H; thrombin; C-reactive protein; receptor for advanced glycation end products
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MDPI and ACS Style

Sridevi Gurubaran, I.; Heloterä, H.; Marry, S.; Koskela, A.; Hyttinen, J.M.T.; Paterno, J.J.; Urtti, A.; Chen, M.; Xu, H.; Kauppinen, A.; Kaarniranta, K. Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3. Biology 2021, 10, 622. https://doi.org/10.3390/biology10070622

AMA Style

Sridevi Gurubaran I, Heloterä H, Marry S, Koskela A, Hyttinen JMT, Paterno JJ, Urtti A, Chen M, Xu H, Kauppinen A, Kaarniranta K. Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3. Biology. 2021; 10(7):622. https://doi.org/10.3390/biology10070622

Chicago/Turabian Style

Sridevi Gurubaran, Iswariyaraja, Hanna Heloterä, Stephen Marry, Ali Koskela, Juha M.T. Hyttinen, Jussi J. Paterno, Arto Urtti, Mei Chen, Heping Xu, Anu Kauppinen, and Kai Kaarniranta. 2021. "Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3" Biology 10, no. 7: 622. https://doi.org/10.3390/biology10070622

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