Nephrin, a transmembrane protein, is involved in pancreatic beta-cell survival signaling

Mol Cell Endocrinol. 2015 Jan 15;400:112-28. doi: 10.1016/j.mce.2014.11.003. Epub 2014 Nov 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Transformed
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Survival / drug effects
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Models, Animal
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glucose / pharmacology
  • Insulin / metabolism
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Leptin / deficiency
  • Receptors, Leptin / genetics
  • Signal Transduction
  • bcl-Associated Death Protein / genetics
  • bcl-Associated Death Protein / metabolism

Substances

  • Antibodies, Monoclonal
  • Bad protein, mouse
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Insulin
  • Membrane Proteins
  • Receptors, Leptin
  • bcl-Associated Death Protein
  • leptin receptor, mouse
  • nephrin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C-alpha
  • Glucose