Depletion of the Third Complement Component Ameliorates Age-Dependent Oxidative Stress and Positively Modulates Autophagic Activity in Aged Retinas in a Mouse Model.

Dorota Rogińska,Renata Lejkowska,Christian A Schmidt,Bogusław Machaliński,Jussi J Paterno,Karolina Łuczkowska,Anna Machalińska,Miłosz P Kawa,Barbara Wiszniewska,Ewa Pius-Sadowska,Kai Kaarniranta

doi:10.1155/2017/5306790

Abstract

The aim of the study was to investigate the influence of complement component C3 global depletion on the biological structure and function of the aged retina. In vivo morphology (OCT), electrophysiological function (ERG), and the expression of selected oxidative stress-, apoptosis-, and autophagy-related proteins were assessed in retinas of 12-month-old C3-deficient and WT mice. Moreover, global gene expression in retinas was analyzed by RNA arrays. We found that the absence of active C3 was associated with (1) alleviation of the age-dependent decrease in retinal thickness and gradual deterioration of retinal bioelectrical function, (2) significantly higher levels of antioxidant enzymes (catalase and glutathione reductase) and the antiapoptotic survivin and Mcl-1/Bak dimer, (3) lower expression of the cellular oxidative stress marker—4HNE—and decreased activity of proapoptotic caspase-3, (4) ameliorated retinal autophagic activity with localization of ubiquitinated protein conjugates commonly along the retinal pigment epithelium (RPE) layer, and (5) significantly increased expression of several gene sets associated with maintenance of the physiological functions of the neural retina. Our findings shed light on mechanisms of age-related retinal alterations by identifying C3 as a potential therapeutic target for retinal aging.

Highlights

Age-related deterioration of the retina seriously constrains the vision quality of a growing number of elderly people worldwide
To assess whether complement component C3 deficiency influenced the physiological function of aged retinas, we examined the retinal bioelectrical response in 3- and 12-month-old C3-deficient (C3−/−) and control (wild type (WT)) mice
The retina is constantly challenged by excessive formation of reactive oxygen species (ROS) due to the high metabolic rate (i), high oxygen consumption (ii), long periods of exposure to short-wavelength light (iii), high concentration of polyunsaturated fatty acids (PUFAs) (iv), and phagocytic activity of retinal pigment epithelium (RPE) cells, which is accompanied by a respiratory burst—a rapid release of superoxide radical and hydrogen peroxide (v) [14,15,16]

Summary

Introduction

Age-related deterioration of the retina seriously constrains the vision quality of a growing number of elderly people worldwide. The dysregulation of inflammatory and immune pathways has become increasingly accepted as key fundamental mechanisms of age-related retinal alterations [1]. It is widely accepted that age-related retinal cell injury caused by accumulative oxidative stress (OS) represents an initial determinant for various age-related retinal malfunctions. Oxidative stress-related cellular products develop as a consequence of autophagy dysregulation in RPE cells. A large amount of evidence indicates that autophagy declines with age and that this progressive reduction may have a causative role in the development of age-related retinal alterations [3]. Abnormal autophagic and ubiquitin-proteasome pathway (UPP) cleansing has been documented in aged RPE cells and in retinas from AMD patients [3,4,5]

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