Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of
Rapamycin Signaling Independently of Insulin Receptor.
Authors 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 PO, Oh J, Huber TB, Fornoni A
Submitted By Alessia Fornoni on 11/9/2015
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2015
Date Published 9/1/2015
Volume : Pages Not Specified : Not Specified
PubMed Reference 26400569
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 ß-cell
survival. However, this role is incompletely characterized. In this study, we
developed floxed nephrin mice for pancreatic ß-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 ß-cell nutrient sensing in the fasting state and the potential of
nephrin as a drug target in diabetes.