Nephrin—signature molecule of the glomerular podocyte?

Abstract

In recent years there has been an explosion of interest in the glomerular podocyte, which plays a central role in control of glomerular filtration. A host of new molecules have been identified as playing essential roles in the maintenance of podocyte integrity in both humans and mouse models. Of all of these, arguably the most pivotal is nephrin, a transmembrane receptor molecule located at the specialized podocyte cell-cell junction, termed the slit diaphragm. Mutations in this gene cause the most severe form of congenital nephrotic syndrome, and many interacting proteins have now been described to form a large multiprotein complex with complex dynamics. There is little evidence of functional nephrin expression outside the glomerulus, and there are accumulating data that nephrin is essential for the unique properties of podocyte biology. Utilizing a powerful human cell culture model, comparing wild-type with nephrin-null podocytes, we can show that several crucial functional properties of podocytes depend on nephrin, including insulin responsiveness and cytoskeletal reorganization. Thus, it is reasoned that nephrin is a signature molecule required to define distinct podocyte characteristics.

MAGI-2 scaffold protein is critical for kidney barrier function

“…2C). This finding is consistent with early down-regulation of nephrin during disassembly of the slit diaphragm in many cases of glomerular disease without genetic disruption of NPHS1 (14). In contrast, other essential slit diaphragm-associated proteins, such as podocin (27), CD2AP (28), and α-actinin-4 (29) remained unchanged at this time point.…”

“…MAGI-2 was also identified in a multiprotein complex in rat kidney glomeruli, where it interacts with nephrin (13), a transmembrane signaling receptor and essential component of the slit diaphragm, a specialized cell-cell junction that prevents urinary protein loss (14,15). The filtration barrier of the kidney is a highly specialized structure, composed of glomerular endothelial cells, glomerular basement membrane, and interdigitating podocyte foot processes bridged by the slit diaphragm protein complex (16).…”

“…The integrity of this barrier to maintain ultrafiltration of plasma depends on the proper expression and signaling of the components of the slit diaphragm (16)(17)(18). Several mutations in the gene that encodes nephrin (NPHS1), and other components of the slit diaphragm complex, have been described in patients with congenital nephrotic syndrome (14,19).…”

Novel Role of NOD2 in Mediating Ca 2+ Signaling

“…24,25 Although acting as an adhesion molecule, nephrin is a pivotal regulator of podocyte intracellular signaling, 26 which is important in downstream Phosphatidylinositide 3-kinase signaling and a negative regulator of nuclear factor-κB activity. TRPC6 interactions with nephrin near the slit diaphragm may underlie regulation of gating and trafficking of these channels and studies have reported that nephrin plays a role in modulating TRPC6 channel opening.…”

Life Without Nephrin

“…After its discovery, nephrin became a major focus of research efforts around the world and was recently referred to as the signature molecule of the glomerular podocyte. 3 It has been reported that nephrin is a required structural component of the glomerular slit diaphragm; forms a pore structure capable of restricting the passage of albumin-sized molecules; binds numerous other proteins that are both present at the slit diaphragm and required for a proper filtration barrier; and is a lipid raft-associated signaling molecule at the slit diaphragm that undergoes tyrosine phosphorylation and is linked to the actin cytoskeleton within podocyte foot processes. [4][5][6] Although many questions still remain, these results provide important mechanistic insights into the potential roles of nephrin and the slit diaphragm in maintaining podocyte health and in establishing and maintaining a size-selective barrier to albumin.…”