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

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.

Kin of IRRE-like Protein 2 Is a Phosphorylated Glycoprotein That Regulates Basal Insulin Secretion

“…More recently, tyrosine phosphorylation of nephrin was shown to be altered by glucose (59). In this study, we have demonstrated that Kirrel2 is also regulated by post-translational modifications.…”

Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms

“…The presence of nephrin in pancreatic b-cells has been appreciated for more than a decade (7), but only more recently has the protein been identified as being a key regulator of glucose-stimulated insulin secretion (GSIS) (8) and b-cell viability (9). Because nephrin does not possess a natural ligand (10), efforts to therapeutically alter its actions are best addressed through posttranslational modification of the protein.…”

Anti-oxidant, anti-apoptotic, anti-hypoxic and anti-inflammatory conditions induced by PTY-2 against STZ-induced stress in islets

“…Hyperglycemia also impairs nephrin signaling by increasing its internalization and the up-regulation of PKC-α expression, thus, playing an interesting role against gradual pancreatic β -cell loss in T2DM [29].…”

“…Nephrin, a member of immunoglobulin super family, is a surface receptor that is specifically expressed in kidney, brain and pancreas [28]. In the beta cells of islet of Langerhans of pancreas, nephrin plays an important role in beta cell survival signaling through the association with PI3-kinase in mouse islet β -cells and mouse pancreatic beta-cell line (βTC-6 cells) [29]. VEGF is a vital regulator of vascularization of islet cells, and the islet vascular system is critical for a normal section of insulin [30,31].…”