Nephrin contributes to insulin secretion and affects mammalian target of rapamycin signaling independently of insulin receptor

Rodrigo Villarreal, Alla Mitrofanova, Dony Maiguel, Ximena Morales, Jongmin Jeon, Florian Grahammer, Ingo B. Leibiger, Johanna Guzman, Alberto Fachado, TaeHyun Yoo, Anja Busher Katin, Jutta Gellermann, Sandra Merscher, George W. Burke, Per Olof Berggren, Jun Oh, Tobias B. Huber, Alessia Fornoni

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1029-1041
Number of pages13
JournalJournal of the American Society of Nephrology
Volume27
Issue number4
DOIs
Publication statusPublished - 2016 Jan 1

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Insulin Receptor
Sirolimus
Insulin
Podocytes
Glucose Intolerance
nephrin
Autocrine Communication
Phosphorylation
70-kDa Ribosomal Protein S6 Kinases
Nephrotic Syndrome
Phosphatidylinositols
Metabolic Networks and Pathways
Islets of Langerhans
Cell Adhesion
Fasting
Cell Survival
Food
Mutation

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Villarreal, Rodrigo ; Mitrofanova, Alla ; Maiguel, Dony ; Morales, Ximena ; Jeon, Jongmin ; Grahammer, Florian ; Leibiger, Ingo B. ; Guzman, Johanna ; Fachado, Alberto ; Yoo, TaeHyun ; Katin, Anja Busher ; Gellermann, Jutta ; Merscher, Sandra ; Burke, George W. ; Berggren, Per Olof ; Oh, Jun ; Huber, Tobias B. ; Fornoni, Alessia. / Nephrin contributes to insulin secretion and affects mammalian target of rapamycin signaling independently of insulin receptor. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 4. pp. 1029-1041.
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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.",
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Villarreal, R, Mitrofanova, A, Maiguel, D, Morales, X, Jeon, J, Grahammer, F, Leibiger, IB, Guzman, J, Fachado, A, Yoo, T, Katin, AB, Gellermann, J, Merscher, S, Burke, GW, Berggren, PO, Oh, J, Huber, TB & Fornoni, A 2016, 'Nephrin contributes to insulin secretion and affects mammalian target of rapamycin signaling independently of insulin receptor', Journal of the American Society of Nephrology, vol. 27, no. 4, pp. 1029-1041. https://doi.org/10.1681/ASN.2015020210

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, TaeHyun; Katin, Anja Busher; Gellermann, Jutta; Merscher, Sandra; Burke, George W.; Berggren, Per Olof; Oh, Jun; Huber, Tobias B.; Fornoni, Alessia.

In: Journal of the American Society of Nephrology, Vol. 27, No. 4, 01.01.2016, p. 1029-1041.

Research output: Contribution to journalArticle

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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, TaeHyun

AU - Katin, Anja Busher

AU - Gellermann, Jutta

AU - Merscher, Sandra

AU - Burke, George W.

AU - Berggren, Per Olof

AU - Oh, Jun

AU - Huber, Tobias B.

AU - Fornoni, Alessia

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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.

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