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High Glucose Impairs Expression and Activation of MerTK in ARPE-19 Cells.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2022 Jan 20; Vol. 23 (3). Date of Electronic Publication: 2022 Jan 20. - Publication Year :
- 2022
-
Abstract
- MerTK (Mer Tyrosine Kinase) is a cell surface receptor that regulates phagocytosis of photoreceptor outer segments (POS) in retinal pigment epithelial (RPE) cells. POS phagocytosis is impaired in several pathologies, including diabetes. In this study, we investigate whether hyperglycemic conditions may affect MerTK expression and activation in ARPE-19 cells, a retinal pigment epithelial cellular model. ARPE-19 cells were cultured in standard (CTR) or high-glucose (HG) medium for 24 h. Then, we analyzed: mRNA levels and protein expression of MerTK and ADAM9, a protease that cleaves the extracellular region of MerTK; the amount of cleaved Mer (sMer); and the ability of GAS6, a MerTK ligand, to induce MerTK phosphorylation. Since HG reduces miR-126 levels, and ADAM9 is a target of miR-126, ARPE-19 cells were transfected with miR-126 inhibitor or mimic; then, we evaluated ADAM9 expression, sMer, and POS phagocytosis. We found that HG reduced expression and activation of MerTK. Contextually, HG increased expression of ADAM9 and the amount of sMer. Overexpression of miR-126 reduced levels of sMer and improved phagocytosis in ARPE-19 cells cultured with HG. In this study, we demonstrate that HG compromises MerTK expression and activation in ARPE-19 cells. Our results suggest that HG up-regulates ADAM9 expression, leading to increased shedding of MerTK. The consequent rise in sMer coupled to reduced expression of MerTK impairs binding and internalization of POS in ARPE-19 cells.
- Subjects :
- Cell Culture Techniques
Cell Line
Down-Regulation
Enzyme Activation drug effects
Gene Expression Regulation drug effects
Humans
Intercellular Signaling Peptides and Proteins metabolism
MicroRNAs genetics
Phagocytosis
Phosphorylation
Retinal Photoreceptor Cell Outer Segment metabolism
Retinal Pigment Epithelium drug effects
Retinal Pigment Epithelium metabolism
ADAM Proteins genetics
ADAM Proteins metabolism
Glucose adverse effects
Membrane Proteins genetics
Membrane Proteins metabolism
Retinal Pigment Epithelium cytology
c-Mer Tyrosine Kinase genetics
c-Mer Tyrosine Kinase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 23
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 35163068
- Full Text :
- https://doi.org/10.3390/ijms23031144