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

Iswariyaraja Sridevi Gurubaran, Hanna Heloterä, Stephen Marry, Ali Koskela, Juha M. T. Hyttinen, Jussi J. Paterno, Arto Urtti, Mei Chen, Heping Xu, Anu Kauppinen, Kai Kaarniranta*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Article number622
Number of pages14
JournalBiology
Volume10
Issue number7
DOIs
Publication statusPublished - 04 Jul 2021

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

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