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

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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.

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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All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Villarreal, R., Mitrofanova, A., Maiguel, D., Morales, X., Jeon, J., Grahammer, F., Leibiger, I. B., Guzman, J., Fachado, A., Yoo, T. H., Katin, A. B., 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. Journal of the American Society of Nephrology, 27(4), 1029-1041. https://doi.org/10.1681/ASN.2015020210