PMID- 31026769
OWN - NLM
STAT- MEDLINE
DCOM- 20200303
LR  - 20200309
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 24
DP  - 2019 Jun
TI  - Hyperhomocysteinemia-induced death of retinal ganglion cells: The role of Muller 
      glial cells and NRF2.
PG  - 101199
LID - S2213-2317(19)30318-0 [pii]
LID - 10.1016/j.redox.2019.101199 [doi]
LID - 101199
AB  - Hyperhomocysteinemia (Hhcy), or increased levels of the excitatory amino acid 
      homocysteine (Hcy), is implicated in glaucoma, a disease characterized by 
      increased oxidative stress and loss of retinal ganglion cells (RGCs). Whether 
      Hhcy is causative or merely a biomarker for RGC loss in glaucoma is unknown. Here 
      we analyzed the role of NRF2, a master regulator of the antioxidant response, in 
      Hhcy-induced RGC death in vivo and in vitro. By crossing Nrf2(-/-) mice and two 
      mouse models of chronic Hhcy (Cbs(+/-) and Mthfr(+/-) mice), we generated 
      Cbs(+/-)Nrf2(-/-) and Mthfr(+/-)Nrf2(-/-) mice and performed systematic analysis 
      of retinal architecture and visual acuity followed by assessment of retinal 
      morphometry and gliosis. We observed significant reduction of inner retinal layer 
      thickness and reduced visual acuity in Hhcy mice lacking NRF2. These functional 
      deficits were accompanied by fewer RGCs and increased gliosis. Given the key role 
      of Muller glial cells in maintaining RGCs, we established an ex-vivo indirect 
      co-culture system using primary RGCs and Muller cells. Hhcy-exposure decreased 
      RGC viability, which was abrogated when cells were indirectly cultured with 
      wildtype (WT) Muller cells, but not with Nrf2(-/-) Muller cells. Exposure of WT 
      Muller cells to Hhcy yielded a robust mitochondrial and glycolytic response, 
      which was not observed in Nrf2(-/-) Muller cells. Taken together, the in vivo and 
      in vitro data suggest that deleterious effects of Hhcy on RGCs are likely 
      dependent upon the health of retinal glial cells and the availability of an 
      intact retinal antioxidant response mechanism.
CI  - Copyright (c) 2019. Published by Elsevier B.V.
FAU - Navneet, Soumya
AU  - Navneet S
AD  - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, 
      Augusta University, Augusta, GA, USA.
FAU - Zhao, Jing
AU  - Zhao J
AD  - James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, 
      GA, USA; Department of Ophthalmology, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA.
FAU - Wang, Jing
AU  - Wang J
AD  - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, 
      Augusta University, Augusta, GA, USA.
FAU - Mysona, Barbara
AU  - Mysona B
AD  - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, 
      Augusta University, Augusta, GA, USA; Department of Ophthalmology, Medical 
      College of Georgia, Augusta University, Augusta, GA, USA.
FAU - Barwick, Shannon
AU  - Barwick S
AD  - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, 
      Augusta University, Augusta, GA, USA.
FAU - Ammal Kaidery, Navneet
AU  - Ammal Kaidery N
AD  - Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA; Department of Pediatrics, Medical University of 
      South Carolina, Charleston, SC, USA.
FAU - Saul, Alan
AU  - Saul A
AD  - James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, 
      GA, USA; Department of Ophthalmology, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA.
FAU - Kaddour-Djebbar, Ismail
AU  - Kaddour-Djebbar I
AD  - Department of Physiology, Medical College of Georgia, Augusta University, 
      Augusta, GA, USA; Charlie Norwood VA Medical Center, One Freedom Way, Augusta, 
      GA, 30904, USA.
FAU - Bollag, Wendy B
AU  - Bollag WB
AD  - Department of Physiology, Medical College of Georgia, Augusta University, 
      Augusta, GA, USA; Charlie Norwood VA Medical Center, One Freedom Way, Augusta, 
      GA, 30904, USA.
FAU - Thomas, Bobby
AU  - Thomas B
AD  - Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA; Department of Pediatrics, Medical University of 
      South Carolina, Charleston, SC, USA; Department of Neuroscience, Medical 
      University of South Carolina, Charleston, SC, USA; Department of Drug Discovery, 
      Medical University of South Carolina, Charleston, SC, USA.
FAU - Bollinger, Kathryn E
AU  - Bollinger KE
AD  - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, 
      Augusta University, Augusta, GA, USA; Department of Ophthalmology, Medical 
      College of Georgia, Augusta University, Augusta, GA, USA.
FAU - Smith, Sylvia B
AU  - Smith SB
AD  - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 
      University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, 
      Augusta University, Augusta, GA, USA; Department of Ophthalmology, Medical 
      College of Georgia, Augusta University, Augusta, GA, USA. Electronic address: 
      sbsmith@augusta.edu.
LA  - eng
GR  - R01 EY012830/EY/NEI NIH HHS/United States
GR  - R01 EY027406/EY/NEI NIH HHS/United States
GR  - R01 EY028103/EY/NEI NIH HHS/United States
GR  - R01 NS101967/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190411
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (Biomarkers)
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Cell Count
MH  - Coculture Techniques
MH  - Disease Models, Animal
MH  - Electroretinography
MH  - Ependymoglial Cells/metabolism/pathology
MH  - Glycolysis
MH  - Hyperhomocysteinemia/genetics/*metabolism/*pathology
MH  - Intraocular Pressure
MH  - Mice
MH  - Mice, Knockout
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - Retina/diagnostic imaging/metabolism
MH  - Retinal Ganglion Cells/*metabolism/pathology
PMC - PMC6482349
OTO - NOTNLM
OT  - Cystathionine beta-synthase
OT  - Ganglion cells
OT  - Glaucoma
OT  - Homocysteine
OT  - Hyperhomocysteinemia
OT  - Methylene tetrahydrofolate reductase
OT  - Mouse
OT  - NRF2
OT  - Retina
EDAT- 2019/04/27 06:00
MHDA- 2020/03/04 06:00
PMCR- 2019/04/11
CRDT- 2019/04/27 06:00
PHST- 2019/03/13 00:00 [received]
PHST- 2019/04/05 00:00 [revised]
PHST- 2019/04/10 00:00 [accepted]
PHST- 2019/04/27 06:00 [pubmed]
PHST- 2020/03/04 06:00 [medline]
PHST- 2019/04/27 06:00 [entrez]
PHST- 2019/04/11 00:00 [pmc-release]
AID - S2213-2317(19)30318-0 [pii]
AID - 101199 [pii]
AID - 10.1016/j.redox.2019.101199 [doi]
PST - ppublish
SO  - Redox Biol. 2019 Jun;24:101199. doi: 10.1016/j.redox.2019.101199. Epub 2019 Apr 
      11.