Protection of Retina by αB Crystallin in Sodium Iodate Induced Retinal Degeneration
et al. (2014) Protection of Retina by aB Crystallin in Sodium Iodate Induced Retinal Degeneration. PLoS
ONE 9(5): e98275. doi:10.1371/journal.pone.0098275
Protection of Retina by aB Crystallin in Sodium Iodate Induced Retinal Degeneration
Peng Zhou 0
Ram Kannan 0
Christine Spee 0
Parameswaran G. Sreekumar 0
Guorui Dou 0
David R. Hinton 0
Raghavan Raju, Georgia Regents University, United States of America
0 1 Doheny Eye Institute , Los Angeles , California, United States of America, 2 Departments of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America , 3 Ophthalmology , Keck School of Medicine of the University of Southern California , Los Angeles, California , United States of America
Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. The retinal pigment epithelium (RPE) is a critical site of pathology in AMD and aB crystallin expression is increased in RPE and associated drusen in AMD. The purpose of this study was to investigate the role of aB crystallin in sodium iodate (NaIO3)-induced retinal degeneration, a model of AMD in which the primary site of pathology is the RPE. Dose dependent effects of intravenous NaIO3 (20-70 mg/kg) on development of retinal degeneration (fundus photography) and RPE and retinal neuronal loss (histology) were determined in wild type and aB crystallin knockout mice. Absence of aB crystallin augmented retinal degeneration in low dose (20 mg/kg) NaIO3-treated mice and increased retinal cell apoptosis which was mainly localized to the RPE layer. Generation of reactive oxygen species (ROS) was observed with NaIO3 in mouse and human RPE which increased further after aB crystallin knockout or siRNA knockdown, respectively. NaIO3 upregulated AKT phosphorylation and peroxisome proliferator-activator receptor-c (PPARc) which was suppressed after aB crystallin siRNA knockdown. Further, PPARc ligand inhibited NaIO3-induced ROS generation. Our data suggest that aB crystallin plays a critical role in protection of NaIO3-induced oxidative stress and retinal degeneration in part through upregulation of AKT phosphorylation and PPARc expression.
-
Funding: Supported in part by grants EY01545 (DRH) and by core grant EY03040, the Arnold and Mabel Beckman Foundation, and an unrestricted grant to the
Department of Ophthalmology from Research to Prevent Blindness Inc., New York, NY. The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Age-related macular degeneration (AMD) is characterized by
progressive degeneration of the macular region of the retina
resulting in loss of central vision. AMD is the leading cause of
irreversible blindness in the developed world [1]. Clinically, AMD
manifests in two forms; a non-exudative dry form and an
exudative, neovascular wet form [1,2]. Geographic atrophy (GA)
is an advanced form of dry AMD with extensive atrophy and loss
of the retinal pigment epithelium (RPE) and overlying
photoreceptors and is responsible for 1020% of cases of legal blindness
from AMD [3,4]. At present, there is no available effective
treatment for GA.
A number of murine models have been generated that simulate
features of dry AMD including RPE degeneration, lipofuscin
accumulation, subretinal deposits, and loss of photoreceptors [5
12]. Our laboratory recently showed that bone morphogenetic
protein-4 (BMP-4) is highly expressed in dry AMD and mediates
oxidative stress-induced senescence in RPE in in vitro dry AMD
thus serving as a molecular switch between atrophic and
neovascular AMD [13,14]. Localized RPE debridement or
genetic ablation of RPE can lead to a profound reduction in
RPE cells and consequent loss of photoreceptors [15].
Retinotoxicity can also be induced by endogenous and exogenous agents
in laboratory animals. Mice receiving polyinosine-polycytidylic
acid (Poly I: C) had morphological changes similar to that of
humans with dry ARMD exhibiting soft and/or hard Drusen,
GA [16]. Recently, the conditional ablation of the microRNA
processing enzyme DICER1 was shown to induce RPE
degeneration in mice [17]. Genetic or pharmacological inhibition of
inflammasome components (NLRP3, MYD88) was reported to
prevent RPE degeneration induced by DICER1 loss or AluRNA
exposure [18]. While most of the animal models for GA
mentioned above are long-term involving prolonged treatment
regimens, the NaIO3-induced retinal degeneration model has
proven to be a convenient and widely used model, because it is
rapid, reproducible and has a primary site of pathology in the
RPE [6,1922]. Thus, in the present study, we have utilized the
NaIO3 model in 129S6/SvEvTac mice to study mechanisms of
retinal degeneration.
Crystallins are members of the small heat shock protein (sHSP)
family, and aB crystallin has been found to have high (...truncated)