Journal article
Deletion of GLUT1 in mouse lens epithelium leads to cataract formation
Experimental eye research, Vol.172, pp.45-53
07/2018
DOI: 10.1016/j.exer.2018.03.021
PMCID: PMC6716165
PMID: 29604281
Abstract
The primary energy substrate of the lens is glucose and uptake of glucose from the aqueous humor is dependent on glucose transporters. GLUT1, the facilitated glucose transporter encoded by Slc2a1 is expressed in the epithelium of bovine, human and rat lenses. In the current study, we examined the expression of GLUT1 in the mouse lens and determined its role in maintaining lens transparency by studying effects of postnatal deletion of Slc2a1. In situ hybridization and immunofluorescence labeling were used to determine the expression and subcellular distribution of GLUT1 in the lens. Slc2a1 was knocked out of the lens epithelium by crossing transgenic mice expressing Cre recombinase under control of the GFAP promoter with Slc2a1loxP/loxP mice to generate Slc2a1loxP/loxP;GFAP-Cre+/0 (LensΔGlut1) mice. LensΔGlut1 mice developed visible lens opacities by around 3 months of age, which corresponded temporally with the total loss of detectable GLUT1 expression in the lens. Spectral domain optical coherence tomography (SD-OCT) imaging was used to monitor the formation of cataracts over time. SD-OCT imaging revealed that small nuclear cataracts were first apparent in the lenses of LensΔGlut1 mice beginning at about 2.7 months of age. Longitudinal SD-OCT imaging of LensΔGlut1 mice revealed disruption of mature secondary fiber cells after 3 months of age. Histological sections of eyes from LensΔGlut1 mice confirmed the disruption of the secondary fiber cells. The structural changes were most pronounced in fiber cells that had lost their organelles. In contrast, the histology of the lens epithelium in these mice appeared normal. Lactate and ATP were measured in lenses from LensΔGlut1 and control mice at 2 and 3 months of age. At 2 months of age, when GLUT1 was still detectable in the lens epithelium, albeit at low levels, the amount of lactate and ATP were not significantly different from controls. However, in lenses isolated from 3-month-old LensΔGlut1 mice, when GLUT1 was no longer detectable, levels of lactate and ATP were 50% lower than controls. Our findings demonstrate that in vivo, the transparency of mature lens fiber cells was dependent on glycolysis for ATP and the loss of GLUT1 transporters led to cataract formation. In contrast, lens epithelium and cortical fiber cells have mitochondria and could utilize other substrates to support their anabolic and catabolic needs.
•GLUT1 is the primary glucose transporter expressed in the mouse lens epithelium.•Deletion of GLUT1 from the lens epithelium leads to formation of cataracts in mouse lens at the age of approximately 3 months.•Cataract formation is accompanied by a decrease in ATP and lactate levels at 3 months.•Optical Coherence Tomography provides a useful tool for imaging cataract formation.
Details
- Title: Subtitle
- Deletion of GLUT1 in mouse lens epithelium leads to cataract formation
- Creators
- Aditi Swarup - Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA, USABrent A Bell - Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USAJianhai Du - West Virginia University Eye Institute, Morgantown, WV, USAJohn Y.S Han - Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA, USAJamie Soto - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, USAE. Dale Abel - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, USAArturo Bravo-Nuevo - Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USAPaul G FitzGerald - Department of Cell Biology & Human Anatomy, University of California at Davis, Davis, CA, USANeal S Peachey - Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USANancy J Philp - Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Resource Type
- Journal article
- Publication Details
- Experimental eye research, Vol.172, pp.45-53
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/j.exer.2018.03.021
- PMID
- 29604281
- PMCID
- PMC6716165
- ISSN
- 0014-4835
- eISSN
- 1096-0007
- Grant note
- DOI: 10.13039/100008136, name: Case Western Reserve University, award: HL087947, P30 EY025585, R01 EY012042, R01 EY024549, P30 EY012576, I01 BX002340; DOI: 10.13039/501100000850, name: National Heart and Lung Institute, award: HL087947, P30 EY025585, R01 EY012042, R01 EY024549, P30 EY012576, I01 BX002340; DOI: 10.13039/100000053, name: National Eye Institute, award: HL087947, P30 EY025585, R01 EY012042, R01 EY024549, P30 EY012576, I01 BX002340; DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs, award: HL087947, P30 EY025585, R01 EY012042, R01 EY024549, P30 EY012576, I01 BX002340
- Language
- English
- Date published
- 07/2018
- 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
- 9984024539802771
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