LRP1 mediates the IGF-1-induced GLUT1 expression on the cell surface and glucose uptake in M\xfcller glial cells

Virginia Actis Dato,María Cecilia Sánchez,Gustavo Alberto Chiabrando

doi:10.1038/s41598-021-84090-3

Abstract

Insulin-like Growth Factor-1 (IGF-1) is involved in the normal development and survival of retinal cells. Low-density lipoprotein Receptor-related Protein-1 (LRP1) plays a key role on the regulation of several membrane proteins, such as the IGF-1 receptor (IGF-1R). In brain astrocytes, LRP1 interact with IGF-1R and the glucose transporter type 1 (GLUT1), regulating the glucose uptake in these cells. Although GLUT1 is expressed in retinal Müller Glial Cells (MGCs), its regulation is not clear yet. Here, we investigated whether IGF-1 modulates GLUT1 traffic to plasma membrane (PM) and glucose uptake, as well as the involvement of LRP1 in this process in the human Müller glial-derived cell line (MIO-M1). We found that IGF-1 produced GLUT1 translocation to the PM, in a time-dependent manner involving the intracellular signaling activation of MAPK/ERK and PI3K/Akt pathways, and generated a significant glucose uptake. Moreover, we found a molecular association between LRP1 and GLUT1, which was significantly reduced by IGF-1. Finally, cells treated with specific siRNA for LRP1 showed an impaired GLUT1 expression on PM and decreased glucose uptake induced by IGF-1. We conclude that IGF-1 regulates glucose homeostasis in MGCs involving the expression of LRP1.

Highlights

Abbreviations Akt or PKB Protein kinase B p-Akt Phospho-Akt ERK Extracellular signal-regulated kinase p-ERK Phospho-ERK glucose transporter type 1 (GLUT1) Glucose transporter type 1 IGF-1 Insulin-like growth factor-1 MGCs Müller glial cells lipoprotein Receptor-related Protein-1 (LRP1) Low-density lipoprotein receptor-related protein-1 PI3K Phosphatidylinositol-4,5-bisphosphate 3-kinase siRNA Small interference RNA 2-NBDG (2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) Amino)-2-Deoxyglucose
The expressions of GLUT2 and GLUT4 were weakly detected in MIO-M1 cells, these proteins shown a different pattern of distribution compared to GLUT1 in mouse retina (Fig. 1c)
Several reports indicated that GLUT1 is the main glucose transporter in different cells of the retina, included retinal pigment epithelium (RPE), photoreceptors and blood-retinal b arrier[8,32,33,34,35], the regulation in MGCs is not clearly established yet

Summary

Introduction

Abbreviations Akt or PKB Protein kinase B p-Akt Phospho-Akt ERK Extracellular signal-regulated kinase p-ERK Phospho-ERK GLUT1 Glucose transporter type 1 IGF-1 Insulin-like growth factor-1 MGCs Müller glial cells LRP1 Low-density lipoprotein receptor-related protein-1 PI3K Phosphatidylinositol-4,5-bisphosphate 3-kinase siRNA Small interference RNA 2-NBDG (2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) Amino)-2-Deoxyglucose. The Low-density lipoprotein Receptor-related Protein-1 (LRP1) is an endocytic receptor involved in multiple signaling pathways by its ability to interact and regulate the function of others cell surface receptors in several tissues[20,21,22]. In this way, it has been demonstrated that LRP1 interacts with insulin receptor (IR) and regulates insulin-induced intracellular signaling and glucose uptake in the brain and cardiomyocytes[23,24]. GLUT1 is the main glucose transporter in the retina, the regulation of its intracellular traffic and activity in this tissue remains slightly explored

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Results

Conclusion