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J Am Soc Nephrol. 2016 Apr;27(4):1029-41. doi: 10.1681/ASN.2015020210. Epub 2015 Sep 23.

Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor.

Author information

1
Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;
2
Katz Family Drug Discovery Center, Division of Nephrology and Hypertension and.
3
Renal Division, University Hospital Freiburg, Freiburg, Germany;
4
Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden;
5
Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida;
6
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;
7
Pediatric Nephrology, Pediatrics II, University Children's Hospital Essen, Essen, Germany;
8
Department of Pediatric Nephrology, Charité Children's Hospital, Berlin, Germany;
9
Department of Surgery, University of Miami, Miami, Florida; and.
10
Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida; Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden;
11
Pediatric Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
12
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.

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.

KEYWORDS:

diabetes; metabolism; nephrin; signaling

PMID:
26400569
PMCID:
PMC4814188
DOI:
10.1681/ASN.2015020210
[Indexed for MEDLINE]
Free PMC Article

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