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

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Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor. / Villarreal, Rodrigo; Mitrofanova, Alla; Maiguel, Dony; Morales, Ximena; Jeon, Jongmin; Grahammer, Florian; Leibiger, Ingo B; Guzman, Johanna; Fachado, Alberto; Yoo, Tae H; Busher Katin, Anja; Gellermann, Jutta; Merscher, Sandra; Burke, George W; Berggren, Per-Olof; Oh, Jun; Huber, Tobias B; Fornoni, Alessia.

In: J AM SOC NEPHROL, Vol. 27, No. 4, 04.2016, p. 1029-41.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Villarreal, R, Mitrofanova, A, Maiguel, D, Morales, X, Jeon, J, Grahammer, F, Leibiger, IB, Guzman, J, Fachado, A, Yoo, TH, Busher Katin, A, Gellermann, J, Merscher, S, Burke, GW, Berggren, P-O, Oh, J, Huber, TB & Fornoni, A 2016, 'Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor', J AM SOC NEPHROL, vol. 27, no. 4, pp. 1029-41. https://doi.org/10.1681/ASN.2015020210

APA

Villarreal, R., Mitrofanova, A., Maiguel, D., Morales, X., Jeon, J., Grahammer, F., Leibiger, I. B., Guzman, J., Fachado, A., Yoo, T. H., Busher Katin, A., Gellermann, J., Merscher, S., Burke, G. W., Berggren, P-O., Oh, J., Huber, T. B., & Fornoni, A. (2016). Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor. J AM SOC NEPHROL, 27(4), 1029-41. https://doi.org/10.1681/ASN.2015020210

Vancouver

Villarreal R, Mitrofanova A, Maiguel D, Morales X, Jeon J, Grahammer F et al. Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor. J AM SOC NEPHROL. 2016 Apr;27(4):1029-41. https://doi.org/10.1681/ASN.2015020210

Bibtex

@article{cb552ce36f96493fbe475c3387911199,
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.",
keywords = "Adolescent, Animals, Child, Female, Humans, Insulin, Insulin-Secreting Cells, Male, Membrane Proteins, Mice, Phosphorylation, Podocytes, Receptor, Insulin, Signal Transduction, TOR Serine-Threonine Kinases",
author = "Rodrigo Villarreal and Alla Mitrofanova and Dony Maiguel and Ximena Morales and Jongmin Jeon and Florian Grahammer and Leibiger, {Ingo B} and Johanna Guzman and Alberto Fachado and Yoo, {Tae H} and {Busher Katin}, Anja and Jutta Gellermann and Sandra Merscher and Burke, {George W} and Per-Olof Berggren and Jun Oh and Huber, {Tobias B} and Alessia Fornoni",
note = "Copyright {\textcopyright} 2016 by the American Society of Nephrology.",
year = "2016",
month = apr,
doi = "10.1681/ASN.2015020210",
language = "English",
volume = "27",
pages = "1029--41",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "4",

}

RIS

TY - JOUR

T1 - Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor

AU - Villarreal, Rodrigo

AU - Mitrofanova, Alla

AU - Maiguel, Dony

AU - Morales, Ximena

AU - Jeon, Jongmin

AU - Grahammer, Florian

AU - Leibiger, Ingo B

AU - Guzman, Johanna

AU - Fachado, Alberto

AU - Yoo, Tae H

AU - Busher Katin, Anja

AU - Gellermann, Jutta

AU - Merscher, Sandra

AU - Burke, George W

AU - Berggren, Per-Olof

AU - Oh, Jun

AU - Huber, Tobias B

AU - Fornoni, Alessia

N1 - Copyright © 2016 by the American Society of Nephrology.

PY - 2016/4

Y1 - 2016/4

N2 - 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.

AB - 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.

KW - Adolescent

KW - Animals

KW - Child

KW - Female

KW - Humans

KW - Insulin

KW - Insulin-Secreting Cells

KW - Male

KW - Membrane Proteins

KW - Mice

KW - Phosphorylation

KW - Podocytes

KW - Receptor, Insulin

KW - Signal Transduction

KW - TOR Serine-Threonine Kinases

U2 - 10.1681/ASN.2015020210

DO - 10.1681/ASN.2015020210

M3 - SCORING: Journal article

C2 - 26400569

VL - 27

SP - 1029

EP - 1041

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 4

ER -