PMID- 36036912
OWN - NLM
STAT- MEDLINE
DCOM- 20220831
LR  - 20220914
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 63
IP  - 9
DP  - 2022 Aug 2
TI  - Dependence of Retinal Pigment Epithelium Integrity on the NRF2-Heme Oxygenase-1 
      Axis.
PG  - 30
LID - 10.1167/iovs.63.9.30 [doi]
LID - 30
AB  - PURPOSE: Tight junctions (TJs) form the structural basis of retinal pigment 
      epithelium (RPE) barrier functions. Although oxidative stress contributes to 
      age-related macular degeneration, it is unclear how RPE TJ integrity is 
      controlled by redox balance. In this study, we investigated the protective roles 
      of nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor, 
      and heme oxygenase-1 (HO1), a heme-degrading enzyme encoded by the NRF2 target 
      gene HMOX1. METHODS: ARPE19 cell cultures and mice, including wild-type, Nrf2-/-, 
      and RPE-specific NRF2-deficient mice, were treated with chemicals that impose 
      oxidative stress or impact heme metabolism. In addition, NRF2 and HO1 expression 
      in ARPE19 cells was knocked down by siRNA. TJ integrity was examined by 
      anti-zonula occludens-1 staining of cultured cells or flatmount RPE tissues from 
      mice. RPE barrier functions were evaluated by transepithelium electrical 
      resistance in ARPE19 cells and immunofluorescence staining for albumin or dextran 
      in eye histological sections. RESULTS: TJ structures and RPE barrier functions 
      were compromised due to oxidant exposure and NRF2 deficiency but were rescued by 
      HO1 inducer. Furthermore, treatment with HO1 inhibitor or heme precursor is 
      destructive to TJ structures and RPE barrier properties. Interestingly, both NRF2 
      and HO1 were upregulated under oxidative stress, probably as an adaptive response 
      to mitigate oxidant-inflicted damages. CONCLUSIONS: Our data indicate that the 
      NRF2-HO1 axis protects TJ integrity and RPE barrier functions by driving heme 
      degradation.
FAU - Jiang, Yida
AU  - Jiang Y
AD  - Center for Vascular Biology, University of Connecticut Health Center, Farmington, 
      Connecticut, United States.
AD  - Department of Cell Biology, University of Connecticut Health Center, Farmington, 
      Connecticut, United States.
FAU - Duan, Li-Juan
AU  - Duan LJ
AD  - Center for Vascular Biology, University of Connecticut Health Center, Farmington, 
      Connecticut, United States.
FAU - Pi, Jingbo
AU  - Pi J
AD  - School of Public Health, China Medical University, Shenyang, Liaoning, China.
FAU - Le, Yun-Zheng
AU  - Le YZ
AD  - Departments of Medicine, Cell Biology, and Ophthalmology and Harold Hamm Oklahoma 
      Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, 
      Oklahoma, United States.
FAU - Fong, Guo-Hua
AU  - Fong GH
AD  - Center for Vascular Biology, University of Connecticut Health Center, Farmington, 
      Connecticut, United States.
AD  - Department of Cell Biology, University of Connecticut Health Center, Farmington, 
      Connecticut, United States.
LA  - eng
GR  - R01 EY019721/EY/NEI NIH HHS/United States
GR  - R01 EY031593/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Oxidants)
RN  - 42VZT0U6YR (Heme)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
SB  - IM
MH  - Animals
MH  - Heme/metabolism/pharmacology
MH  - Heme Oxygenase-1/genetics/metabolism
MH  - Mice
MH  - *NF-E2-Related Factor 2/metabolism
MH  - Oxidants/pharmacology
MH  - Oxidative Stress/physiology
MH  - *Retinal Pigment Epithelium/pathology
PMC - PMC9434985
COIS- Disclosure: Y. Jiang, None; L.-J. Duan, None; J. Pi, None; Y.-Z. Le, None; G.-H. 
      Fong, None
EDAT- 2022/08/30 06:00
MHDA- 2022/09/01 06:00
PMCR- 2022/08/29
CRDT- 2022/08/29 11:33
PHST- 2022/08/29 11:33 [entrez]
PHST- 2022/08/30 06:00 [pubmed]
PHST- 2022/09/01 06:00 [medline]
PHST- 2022/08/29 00:00 [pmc-release]
AID - 2783610 [pii]
AID - IOVS-22-35171 [pii]
AID - 10.1167/iovs.63.9.30 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2022 Aug 2;63(9):30. doi: 10.1167/iovs.63.9.30.