Polarized retinal pigment epithelium generates electrical signals that diminish with age and regulate retinal pathology

Lin Cao, Jie Liu, Jin Pu, Gillian Milne, Mei Chen, Heping Xu, Alan Shipley, John V Forrester, Colin D. McCaig (Corresponding Author), Noemi Lois (Corresponding Author)

Research output: Contribution to journalArticle

5 Downloads (Pure)

Abstract

The transepithelial potential difference (TEP) across the retinal pigment epithelial (RPE) is dependent on ionic pumps and tight junction “seals” between epithelial cells. RPE cells release neurotrophic growth factors such as pigment epithelial derived factor (PEDF), which is reduced in age‐related macular degeneration (AMD). The mechanisms that control the secretion of PEDF from RPE cells are not well understood. Using the CCL2/CX3CR1 double knockout mouse model (DKO), which demonstrates RPE damage and retinal degeneration, we uncovered an interaction between PEDF and the TEP which is likely to play an important role in retinal ageing and in the pathogenesis of AMD. We found that: (a) the expression of ATP1B1 (the Na+/K+‐ATPase β1 subunit) was reduced significantly in RPE from aged mice, in patients with CNV (Choroidal Neovascularization) and in DKO mice; (b) the expression of PEDF also was decreased in aged persons and in DKO mice; (c) the TEP across RPE was reduced markedly in RPE cells from DKO mice and (d) an applied electric field (EF) of 50‐100 mV/mm, used to mimic the natural TEP, increased the expression and secretion of PEDF in primary RPE cells. In conclusion, the TEP across the RPE depends on the expression of ATP1B1 and this regulates the secretion of PEDF by RPE cells and so may regulate the onset of retinal disease. Increasing the expression of PEDF using an applied EF to replenish a disease or age‐reduced TEP may offer a new way of preventing or reversing retinal dysfunction.

Original languageEnglish
Pages (from-to)5552-5564
Number of pages13
JournalJournal of Cellular and Molecular Medicine
Volume22
Issue number11
Early online date30 Aug 2018
DOIs
Publication statusPublished - Nov 2018

Fingerprint

Retinal Pigments
Retinal Pigment Epithelium
Pathology
Epithelial Cells
Macular Degeneration
Retinal Diseases
Choroidal Neovascularization
Retinal Degeneration
Tight Junctions
Nerve Growth Factors
Knockout Mice
Intercellular Signaling Peptides and Proteins

Keywords

  • ATP1B1
  • CCL2/CX3CR1 double knockout mice
  • cell‐cell connection
  • extracellular electrical signalling

Cite this

@article{1fae5e2272b34459b28b060add5246e2,
title = "Polarized retinal pigment epithelium generates electrical signals that diminish with age and regulate retinal pathology",
abstract = "The transepithelial potential difference (TEP) across the retinal pigment epithelial (RPE) is dependent on ionic pumps and tight junction “seals” between epithelial cells. RPE cells release neurotrophic growth factors such as pigment epithelial derived factor (PEDF), which is reduced in age‐related macular degeneration (AMD). The mechanisms that control the secretion of PEDF from RPE cells are not well understood. Using the CCL2/CX3CR1 double knockout mouse model (DKO), which demonstrates RPE damage and retinal degeneration, we uncovered an interaction between PEDF and the TEP which is likely to play an important role in retinal ageing and in the pathogenesis of AMD. We found that: (a) the expression of ATP1B1 (the Na+/K+‐ATPase β1 subunit) was reduced significantly in RPE from aged mice, in patients with CNV (Choroidal Neovascularization) and in DKO mice; (b) the expression of PEDF also was decreased in aged persons and in DKO mice; (c) the TEP across RPE was reduced markedly in RPE cells from DKO mice and (d) an applied electric field (EF) of 50‐100 mV/mm, used to mimic the natural TEP, increased the expression and secretion of PEDF in primary RPE cells. In conclusion, the TEP across the RPE depends on the expression of ATP1B1 and this regulates the secretion of PEDF by RPE cells and so may regulate the onset of retinal disease. Increasing the expression of PEDF using an applied EF to replenish a disease or age‐reduced TEP may offer a new way of preventing or reversing retinal dysfunction.",
keywords = "ATP1B1, CCL2/CX3CR1 double knockout mice, cell‐cell connection, extracellular electrical signalling",
author = "Lin Cao and Jie Liu and Jin Pu and Gillian Milne and Mei Chen and Heping Xu and Alan Shipley and Forrester, {John V} and McCaig, {Colin D.} and Noemi Lois",
note = "Fight for Sight. Grant Numbers: 1712/13, 1361/1362 NHS Grampian Endowments, Friends of ANCHOR, Action Medical Research. Grant Number: GN2299",
year = "2018",
month = "11",
doi = "10.1111/jcmm.13829",
language = "English",
volume = "22",
pages = "5552--5564",
journal = "Journal of Cellular and Molecular Medicine",
issn = "1582-1838",
publisher = "Wiley-Blackwell",
number = "11",

}

TY - JOUR

T1 - Polarized retinal pigment epithelium generates electrical signals that diminish with age and regulate retinal pathology

AU - Cao, Lin

AU - Liu, Jie

AU - Pu, Jin

AU - Milne, Gillian

AU - Chen, Mei

AU - Xu, Heping

AU - Shipley, Alan

AU - Forrester, John V

AU - McCaig, Colin D.

AU - Lois, Noemi

N1 - Fight for Sight. Grant Numbers: 1712/13, 1361/1362 NHS Grampian Endowments, Friends of ANCHOR, Action Medical Research. Grant Number: GN2299

PY - 2018/11

Y1 - 2018/11

N2 - The transepithelial potential difference (TEP) across the retinal pigment epithelial (RPE) is dependent on ionic pumps and tight junction “seals” between epithelial cells. RPE cells release neurotrophic growth factors such as pigment epithelial derived factor (PEDF), which is reduced in age‐related macular degeneration (AMD). The mechanisms that control the secretion of PEDF from RPE cells are not well understood. Using the CCL2/CX3CR1 double knockout mouse model (DKO), which demonstrates RPE damage and retinal degeneration, we uncovered an interaction between PEDF and the TEP which is likely to play an important role in retinal ageing and in the pathogenesis of AMD. We found that: (a) the expression of ATP1B1 (the Na+/K+‐ATPase β1 subunit) was reduced significantly in RPE from aged mice, in patients with CNV (Choroidal Neovascularization) and in DKO mice; (b) the expression of PEDF also was decreased in aged persons and in DKO mice; (c) the TEP across RPE was reduced markedly in RPE cells from DKO mice and (d) an applied electric field (EF) of 50‐100 mV/mm, used to mimic the natural TEP, increased the expression and secretion of PEDF in primary RPE cells. In conclusion, the TEP across the RPE depends on the expression of ATP1B1 and this regulates the secretion of PEDF by RPE cells and so may regulate the onset of retinal disease. Increasing the expression of PEDF using an applied EF to replenish a disease or age‐reduced TEP may offer a new way of preventing or reversing retinal dysfunction.

AB - The transepithelial potential difference (TEP) across the retinal pigment epithelial (RPE) is dependent on ionic pumps and tight junction “seals” between epithelial cells. RPE cells release neurotrophic growth factors such as pigment epithelial derived factor (PEDF), which is reduced in age‐related macular degeneration (AMD). The mechanisms that control the secretion of PEDF from RPE cells are not well understood. Using the CCL2/CX3CR1 double knockout mouse model (DKO), which demonstrates RPE damage and retinal degeneration, we uncovered an interaction between PEDF and the TEP which is likely to play an important role in retinal ageing and in the pathogenesis of AMD. We found that: (a) the expression of ATP1B1 (the Na+/K+‐ATPase β1 subunit) was reduced significantly in RPE from aged mice, in patients with CNV (Choroidal Neovascularization) and in DKO mice; (b) the expression of PEDF also was decreased in aged persons and in DKO mice; (c) the TEP across RPE was reduced markedly in RPE cells from DKO mice and (d) an applied electric field (EF) of 50‐100 mV/mm, used to mimic the natural TEP, increased the expression and secretion of PEDF in primary RPE cells. In conclusion, the TEP across the RPE depends on the expression of ATP1B1 and this regulates the secretion of PEDF by RPE cells and so may regulate the onset of retinal disease. Increasing the expression of PEDF using an applied EF to replenish a disease or age‐reduced TEP may offer a new way of preventing or reversing retinal dysfunction.

KW - ATP1B1

KW - CCL2/CX3CR1 double knockout mice

KW - cell‐cell connection

KW - extracellular electrical signalling

U2 - 10.1111/jcmm.13829

DO - 10.1111/jcmm.13829

M3 - Article

VL - 22

SP - 5552

EP - 5564

JO - Journal of Cellular and Molecular Medicine

JF - Journal of Cellular and Molecular Medicine

SN - 1582-1838

IS - 11

ER -