Modulating GLUT1 expression in retinal pigment epithelium decreases glucose levels in the retina: impact on photoreceptors and Müller glial cells

Aditi Swarup; Ivy S Samuels; Brent A Bell; John Y S Han; Jianhai Du; Erik Massenzio; E Dale Abel; Kathleen Boesze-Battaglia; Neal S Peachey; Nancy J Philp

doi:10.1152/ajpcell.00410.2018

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Modulating GLUT1 expression in retinal pigment epithelium decreases glucose levels in the retina: impact on photoreceptors and Müller glial cells

Journal article

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Peer reviewed

Modulating GLUT1 expression in retinal pigment epithelium decreases glucose levels in the retina: impact on photoreceptors and Müller glial cells

Aditi Swarup, Ivy S Samuels, Brent A Bell, John Y S Han, Jianhai Du, Erik Massenzio, E Dale Abel, Kathleen Boesze-Battaglia, Neal S Peachey and Nancy J Philp

American Journal of Physiology: Cell Physiology, Vol.316(1), pp.C121-C133

01/01/2019

DOI: 10.1152/ajpcell.00410.2018

PMCID: PMC6383144

PMID: 30462537

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Abstract

The retina is one of the most metabolically active tissues in the body and utilizes glucose to produce energy and intermediates required for daily renewal of photoreceptor cell outer segments. Glucose transporter 1 (GLUT1) facilitates glucose transport across outer blood retinal barrier (BRB) formed by the retinal pigment epithelium (RPE) and the inner BRB formed by the endothelium. We used conditional knockout mice to study the impact of reducing glucose transport across the RPE on photoreceptor and Müller glial cells. Transgenic mice expressing Cre recombinase under control of the Bestrophin1 ( Best1) promoter were bred with Glut1 mice to generate Tg-Best1-Cre:Glut1 mice ( RPEΔGlut1). The RPEΔGlut1 mice displayed a mosaic pattern of Cre expression within the RPE that allowed us to analyze mice with ~50% ( RPEΔGlut1 ) recombination and mice with >70% ( RPEΔGlut1 ) recombination separately. Deletion of GLUT1 from the RPE did not affect its carrier or barrier functions, indicating that the RPE utilizes other substrates to support its metabolic needs thereby sparing glucose for the outer retina. RPEΔGlut1 mice had normal retinal morphology, function, and no cell death; however, where GLUT1 was absent from a span of RPE greater than 100 µm, there was shortening of the photoreceptor cell outer segments. RPEΔGlut1 mice showed outer segment shortening, cell death of photoreceptors, and activation of Müller glial cells. The severe phenotype seen in RPEΔGlut1 mice indicates that glucose transport via the GLUT1 transporter in the RPE is required to meet the anabolic and catabolic requirements of photoreceptors and maintain Müller glial cells in a quiescent state.

Gene Expression

Retinal Pigment Epithelium - metabolism

Ependymoglial Cells - chemistry

Ependymoglial Cells - metabolism

Mice, Transgenic

Photoreceptor Cells - chemistry

Mice, Knockout

Retinal Pigment Epithelium - chemistry

Animals

Glucose Transporter Type 1 - biosynthesis

Glucose Transporter Type 1 - genetics

Photoreceptor Cells - metabolism

Glucose - metabolism

Mice

Details

Title: Subtitle: Modulating GLUT1 expression in retinal pigment epithelium decreases glucose levels in the retina: impact on photoreceptors and Müller glial cells
Creators: Aditi Swarup - Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University , Philadelphia, Pennsylvania
Ivy S Samuels - Cole Eye Institute, Cleveland Clinic , Cleveland, Ohio
Brent A Bell - Department of Ophthalmology, University of Pennsylvania , Philadelphia, Pennsylvania
John Y S Han - Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University , Philadelphia, Pennsylvania
Jianhai Du - Department of Ophthalmology, Department of Biochemistry, West Virginia University Eye Institute , Morgantown, West Virginia
Erik Massenzio - Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University , Philadelphia, Pennsylvania
E Dale Abel - Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa , Iowa City, Iowa
Kathleen Boesze-Battaglia - Department of Biochemistry, Penn Dental Medicine, University of Pennsylvania , Philadelphia, Pennsylvania
Neal S Peachey - Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University , Cleveland, Ohio
Nancy J Philp - Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University , Philadelphia, Pennsylvania
Resource Type: Journal article
Publication Details: American Journal of Physiology: Cell Physiology, Vol.316(1), pp.C121-C133
Publisher: United States
DOI: 10.1152/ajpcell.00410.2018
PMID: 30462537
PMCID: PMC6383144
ISSN: 0363-6143
eISSN: 1522-1563
Grant note: I01 BX002754 / BLRD VA T32 AA007463 / NIAAA NIH HHS R01 EY012042 / NEI NIH HHS I01 BX002340 / BLRD VA P30 EY025585 / NEI NIH HHS R01 EY026525 / NEI NIH HHS IK6 BX005233 / BLRD VA
Language: English
Date published: 01/01/2019
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024507702771

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