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 b-cell survival. However, this role is incompletely characterized. In this study, we developed floxed nephrin mice for pancreatic b-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 b-cell nutrient sensing in the fasting state and the potential of nephrin as a drug target in diabetes.

Nephrin Trafficking beyond the Kidney—Role in Glucose–Stimulated Insulin Secretion in β Cells

“…Mice depleted of nephrin in b cells showed no change in body weight and random glycemia or random plasma insulin levels but presented glucose intolerance in vivo and impaired glucose-stimulated release of insulin ex vivo. 12 The absence of pancreatic nephrin had no effect on the size or number of the islets or the b cell mass, and the mice did not develop diabetes. 12 Interestingly, Fornoni and colleagues 12 observed that eight patients with mutations in NPHS1 showed glucose intolerance compared with nine healthy controls and three patients with other genetic forms of nephrotic syndrome.…”

“…12 The absence of pancreatic nephrin had no effect on the size or number of the islets or the b cell mass, and the mice did not develop diabetes. 12 Interestingly, Fornoni and colleagues 12 observed that eight patients with mutations in NPHS1 showed glucose intolerance compared with nine healthy controls and three patients with other genetic forms of nephrotic syndrome. This is in contrast to a previous observation by Kuusniemi et al, 9 who addressed the function of b cells by oral glucose tolerance test in patients with NPHS1 who had received a kidney transplant 1-5 years earlier.…”

“…9 Clinically, patients with NPHS1 do not have extrarenal manifestations, with the exception of reversible cardiac hypertrophy and muscular hypotonia caused by the severe hypoalbuminemia. 2 In an elegant series of works culminating in the study published in this issue of the Journal of the American Society of Nephrology, the group of Fornoni and colleagues [10][11][12] revealed a novel function for nephrin outside podocytes and coupled nephrin to insulin secretion in b cells. Fornoni and colleagues [10][11][12] first confirmed that nephrin is expressed in b cells in human pancreas and showed that nephrin localizes to both the plasma membrane and the surface of insulincontaining vesicles in these cells.…”

“…The Finnish mutations lead to total absence of nephrin protein and the most severe disease manifestation as opposed to the many other mutations, prevailing outside Finland, that often lead to milder outcome. Villareal et al 12 performed glucose tolerance tests in the nephrotic stage when the patients showed heavy proteinuria and renal failure, whereas the previous studies were performed after transplantation in patients with NPHS1 and relatively normal graft function. Because glucose intolerance has been described in patients with proteinuria and impaired renal function for various reasons, 14,15 it is important to compare the results between different groups of patients with renal disease.…”

“…Because glucose intolerance has been described in patients with proteinuria and impaired renal function for various reasons, 14,15 it is important to compare the results between different groups of patients with renal disease. In the study by Villarreal et al, 12 there were eight patients with NPHS1 and three control patients with other proteinuric disorders. Thus, it is obvious that new studies with larger patient populations are needed, which was pointed out by Villarreal et al 12 An interesting observation in the work by Villarreal et al 12 is the finding that nephrin participates in the control of autocrine regulation of insulin secretion by binding to insulin receptor and directly regulating the downstream targets of the cascade.…”