title: Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor.
abstract: Nephrin belongs to a family of highly conserved proteins with a well characterized function as modulators of cell adhesion and guidance, and nephrin may have a role in metabolic pathways linked to podocyte and pancreatic β-cell survival. However, this role is incompletely characterized. In this study, we developed floxed nephrin mice for pancreatic β-cell-specific deletion of nephrin, which had no effect on islet size and glycemia. Nephrin deficiency, however, resulted in glucose intolerance in vivo and impaired glucose-stimulated insulin release ex vivo Glucose intolerance was also observed in eight patients with nephrin mutations compared with three patients with other genetic forms of nephrotic syndrome or nine healthy controls.In vitro experiments were conducted to investigate if nephrin affects autocrine signaling through insulin receptor A (IRA) and B (IRB), which are both expressed in human podocytes and pancreatic islets. Coimmunoprecipitation of nephrin and IRB but not IRA was observed and required IR phosphorylation. Nephrin per se was sufficient to induce phosphorylation of p70S6K in an phosphatidylinositol 3-kinase-dependent but IR/Src-independent manner, which was not augmented by exogenous insulin. These results suggest a role for nephrin as an independent modulator of podocyte and pancreatic β-cell nutrient sensing in the fasting state and the potential of nephrin as a drug target in diabetes.
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Villarreal
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and.
authors.forename: Alla
authors.initials: A
authors.lastname: Mitrofanova
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Dony
authors.initials: D
authors.lastname: Maiguel
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and.
authors.forename: Ximena
authors.initials: X
authors.lastname: Morales
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Jongmin
authors.initials: J
authors.lastname: Jeon
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg, Germany;
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Leibiger
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Johanna
authors.initials: J
authors.lastname: Guzman
authors.affiliation: Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Alberto
authors.initials: A
authors.lastname: Fachado
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and Department of Internal Medicine, Division of Nephrology, Yonsei University College of Medicine, Seoul, Korea;
authors.forename: Tae H
authors.initials: TH
authors.lastname: Yoo
authors.affiliation: Pediatric Nephrology, Pediatrics II, University Children's Hospital Essen, Essen, Germany;
authors.forename: Anja
authors.initials: A
authors.lastname: Busher Katin
authors.affiliation: Department of Pediatric Nephrology, Charité Children's Hospital, Berlin, Germany;
authors.forename: Jutta
authors.initials: J
authors.lastname: Gellermann
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Sandra
authors.initials: S
authors.lastname: Merscher
authors.affiliation: Department of Surgery, University of Miami, Miami, Florida; and.
authors.forename: George W
authors.initials: GW
authors.lastname: Burke
authors.affiliation: Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida; Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: Pediatric Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Oh
authors.affiliation: Renal Division, University Hospital Freiburg, Freiburg, Germany;
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.affiliation: Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida; afornoni@med.miami.edu.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D050199:Podocytes / Q000502:physiology; D011972:Receptor, Insulin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D007328:Insulin; D008565:Membrane Proteins; C113267:nephrin; C546843:mTOR protein, mouse; D011972:Receptor, Insulin; D058570:TOR Serine-Threonine Kinases
keywords: diabetes; metabolism; nephrin; signaling