title: 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.
authors.affiliation: Institute of Biosciences and Applications, National Centre for Scientific Research, N.C.S.R. "Demokritos", Terma Patriarchou Grigoriou & Neapoleos, 15310 Agia Paraskevi, Attiki, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kapodistria
authors.affiliation: Institute of Biosciences and Applications, National Centre for Scientific Research, N.C.S.R. "Demokritos", Terma Patriarchou Grigoriou & Neapoleos, 15310 Agia Paraskevi, Attiki, Greece.
authors.forename: Effie-Photini
authors.initials: EP
authors.lastname: Tsilibary
authors.affiliation: Center for Basic Research, Biomedical Research Foundation Academy of Athens (BRFAA), 4 Soranou Ephessiou, Athens 115 27, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Politis
authors.affiliation: Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens (BRFAA), 4 Soranou Ephessiou, Athens 115 27, Greece.
authors.forename: Petros
authors.initials: P
authors.lastname: Moustardas
authors.affiliation: Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens (BRFAA), 4 Soranou Ephessiou, Athens 115 27, Greece.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Charonis
authors.affiliation: Institute of Biosciences and Applications, National Centre for Scientific Research, N.C.S.R. "Demokritos", Terma Patriarchou Grigoriou & Neapoleos, 15310 Agia Paraskevi, Attiki, Greece. Electronic address: pkit@bio.demokritos.gr.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Kitsiou
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C494820:Bad protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D008565:Membrane Proteins; D054411:Receptors, Leptin; D051025:bcl-Associated Death Protein; C515447:leptin receptor, mouse; C113267:nephrin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051571:Protein Kinase C-alpha; D005947:Glucose
keywords: Diabetic mouse pancreatic islets; High glucose; Nephrin internalization; Nephrin signaling; PI3K-Akt survival signaling; Pancreatic β-cells