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Role of oxidative stress in epigenetic modification of MMP-9 promoter in the development of diabetic retinopathy.

Abstract In the pathogenesis of diabetic retinopathy, damaged retinal mitochondria accelerate apoptosis of retinal capillary cells, and regulation of oxidative stress by manipulating mitochondrial superoxide dismutase (SOD2) protects mitochondrial homeostasis and prevents the development of diabetic retinopathy. Diabetes also activates matrix metalloproteinase-9 (MMP-9), and activated MMP-9 damages retinal mitochondria. Recent studies have shown a dynamic DNA methylation process playing an important role in regulation of retinal MMP-9 transcription in diabetes; the aim of this study is to investigate the role of oxidative stress in MMP-9 transcription.
PMID
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Authors

Mayor MeshTerms

Diabetes Mellitus, Experimental

Oxidative Stress

Keywords

DNA methylation

Diabetic retinopathy

Epigenetics

Oxidative stress

Journal Title graefe's archive for clinical and experimental ophthalmology = albrecht von graefes archiv fur klinische und experimentelle ophthalmologie
Publication Year Start




PMID- 28124145
OWN - NLM
STAT- MEDLINE
DCOM- 20170905
LR  - 20170906
IS  - 1435-702X (Electronic)
IS  - 0721-832X (Linking)
VI  - 255
IP  - 5
DP  - 2017 May
TI  - Role of oxidative stress in epigenetic modification of MMP-9 promoter in the
      development of diabetic retinopathy.
PG  - 955-962
LID - 10.1007/s00417-017-3594-0 [doi]
AB  - BACKGROUND: In the pathogenesis of diabetic retinopathy, damaged retinal
      mitochondria accelerate apoptosis of retinal capillary cells, and regulation of
      oxidative stress by manipulating mitochondrial superoxide dismutase (SOD2)
      protects mitochondrial homeostasis and prevents the development of diabetic
      retinopathy. Diabetes also activates matrix metalloproteinase-9 (MMP-9), and
      activated MMP-9 damages retinal mitochondria. Recent studies have shown a dynamic
      DNA methylation process playing an important role in regulation of retinal MMP-9 
      transcription in diabetes; the aim of this study is to investigate the role of
      oxidative stress in MMP-9 transcription. METHODS: The effect of regulation of
      mitochondrial superoxide on DNA methylation of MMP-9 promoter region was
      investigated in retinal endothelial cells incubated in the presence or absence of
      a MnSOD mimetic MnTBAP, by quantifying the levels of 5 methyl cytosine (5mC) and 
      hydroxyl-methyl cytosine (5hmC). The binding of DNA methylating, and of
      hydroxymenthylating enzymes (Dnmts and Tets, respectively), at MMP-9 promoter (by
      chromatin immunoprecipitation) was also evaluated. The in vitro results were
      confirmed in the retina of diabetic mice overexpressing SOD2. RESULTS: MnTBAP
      attenuated glucose-induced decrease in 5mC levels and increase on Dnmt1 binding
      at the MMP-9 promoter region. MnTBAP also ameliorated alterations in 5hmC levels 
      and Tet binding, regulated MMP-9 transcription, and prevented mitochondrial
      damage. Similarly, mice overexpressing SOD2 were protected from diabetes-induced 
      alteration in MMP-9 promoter methylation, and its transcription. CONCLUSIONS:
      Thus, regulation of oxidative stress by pharmacologic/genetic approaches
      maintains retinal mitochondrial homeostasis by ameliorating epigenetic
      modifications in the MMP-9 promoter region.
FAU - Kowluru, Renu A
AU  - Kowluru RA
AD  - Kresge Eye Institute, Wayne State University, Detroit, MI, 48201, USA.
      [email protected]
FAU - Shan, Yang
AU  - Shan Y
AD  - Kresge Eye Institute, Wayne State University, Detroit, MI, 48201, USA.
LA  - eng
GR  - R01 EY014370/EY/NEI NIH HHS/United States
GR  - R01 EY017313/EY/NEI NIH HHS/United States
GR  - R01 EY022230/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20170125
PL  - Germany
TA  - Graefes Arch Clin Exp Ophthalmol
JT  - Graefe's archive for clinical and experimental ophthalmology = Albrecht von
      Graefes Archiv fur klinische und experimentelle Ophthalmologie
JID - 8205248
RN  - 9007-49-2 (DNA)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
EIN - Graefes Arch Clin Exp Ophthalmol. 2017 May;255 (5):1055-1056. PMID: 28246894
MH  - Animals
MH  - Apoptosis
MH  - Cattle
MH  - Cells, Cultured
MH  - DNA/*genetics
MH  - DNA Methylation
MH  - *Diabetes Mellitus, Experimental
MH  - Diabetic Retinopathy/genetics/*metabolism/pathology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Epigenomics/methods
MH  - Matrix Metalloproteinase 9/*genetics/metabolism
MH  - Mice, Transgenic
MH  - Mitochondria/metabolism
MH  - *Oxidative Stress
MH  - Promoter Regions, Genetic
MH  - Real-Time Polymerase Chain Reaction
MH  - Superoxide Dismutase/metabolism
MH  - Transcription, Genetic
PMC - PMC5395319
MID - NIHMS846933
OTO - NOTNLM
OT  - DNA methylation
OT  - Diabetic retinopathy
OT  - Epigenetics
OT  - Oxidative stress
EDAT- 2017/01/27 06:00
MHDA- 2017/09/07 06:00
CRDT- 2017/01/27 06:00
PMCR- 2018/05/01 00:00
PHST- 2016/08/29 00:00 [received]
PHST- 2017/01/16 00:00 [accepted]
PHST- 2016/12/11 00:00 [revised]
PHST- 2018/05/01 00:00 [pmc-release]
PHST- 2017/01/27 06:00 [pubmed]
PHST- 2017/09/07 06:00 [medline]
PHST- 2017/01/27 06:00 [entrez]
AID - 10.1007/s00417-017-3594-0 [doi]
AID - 10.1007/s00417-017-3594-0 [pii]
PST - ppublish
SO  - Graefes Arch Clin Exp Ophthalmol. 2017 May;255(5):955-962. doi:
      10.1007/s00417-017-3594-0. Epub 2017 Jan 25.