Abstract
Nephrin, a cell surface signaling receptor, regulates podocyte function in health and disease. We study the role of nephrin in β-cell survival signaling. We report that in mouse islet β-cells and the mouse pancreatic beta-cell line (βTC-6 cells) nephrin is associated and partly co-localized with PI3-kinase. Incubation of cells with functional anti-nephrin antibodies induced nephrin clustering at the plasma membrane, nephrin phosphorylation and recruitment of PI3-kinase to nephrin thus resulting in increased PI3K-dependent Akt phosphorylation and augmented phosphorylation/inhibition of pro-apoptotic Bad and FoxO. Nephrin silencing abolished Akt activation and increased susceptibility of cells to apoptosis. High glucose impaired nephrin signaling, increased nephrin internalization and up-regulated PKCα expression. Interestingly, a marked decrease in nephrin expression and phosphorylated Akt was observed in pancreatic islets of db/db lepr-/- diabetic mice. Our findings revealed that nephrin is involved in β-cell survival and suggest that glucose-induced changes in nephrin signaling may contribute to gradual pancreatic β-cell loss in type 2 diabetes.
Keywords:
Diabetic mouse pancreatic islets; High glucose; Nephrin internalization; Nephrin signaling; PI3K-Akt survival signaling; Pancreatic β-cells.
Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Line, Transformed
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Cell Survival / drug effects
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism*
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Diabetes Mellitus, Type 2 / pathology
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Disease Models, Animal
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Forkhead Box Protein O1
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation
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Glucose / metabolism
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Glucose / pharmacology
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Insulin / metabolism
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism*
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Insulin-Secreting Cells / pathology
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation / drug effects
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Protein Kinase C-alpha / genetics
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Protein Kinase C-alpha / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Leptin / deficiency
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Receptors, Leptin / genetics
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Signal Transduction
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bcl-Associated Death Protein / genetics
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bcl-Associated Death Protein / metabolism
Substances
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Antibodies, Monoclonal
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Bad protein, mouse
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Insulin
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Membrane Proteins
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Receptors, Leptin
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bcl-Associated Death Protein
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leptin receptor, mouse
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nephrin
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Protein Kinase C-alpha
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Glucose