A Novel Role for Nephrin in the Maintenance of Glomerular Structure
Authors: Neil S. Sheerin
Journal: Journal of the American Society of Nephrology (2009)

The NF-κB family of transcription factors is a key mediator of the immune and inflammatory response to a diverse range of environmental and microbiological targets. The role of NF-κB extends beyond transcriptional control of the immune response, however; it is also involved in maintaining the structure and function of many tissues. To serve such a multitude of functions, NF-κB has developed the capacity to generate transcriptional responses that are both stimulus specific and cell specific. Because of this, NF-κB signaling is a paradigm in cell signaling research. There are five proteins within the NF-κB group, which normally exist as homo- and heterodimers. The dimers are complexed with a member of the IκB family, which is responsible for maintaining the cytoplasmic localization of NF-κB. When cells are activated, IκB is phosphorylated, dissociates from the NF-κB complex, and is degraded. NF-κB then migrates to the nucleus, where it binds to κB consensus sequences controlling the expression of more than 100 genes,1 including many of the genes involved in the immune response. This traditional view of NF-κB biology is an oversimplification, because this is a very dynamic system with constant shuttling of NF-κB between the cytoplasm and the nucleus with the equilibrium in the presence of IκB proteins lying toward cytoplasmic localization. Because of its many effects, it is perhaps not surprising that the activation of NF-κB is implicated in many pathologic conditions. Tight control of NF-κB activation is critical in preventing tissue injury. In any circumstance in which excessive or inappropriate activation of the immune system occurs and tissue injury ensues, NF-κB is probably involved. Inherited variability in control of NF-κB activation is proposed as the cause of some autoinflammatory diseases,2 suggesting that activation of NF-κB alone in the absence of other stimuli can be harmful. Excess activation of NF-κB is typically present in inflammatory renal diseases,3 and, in animal models, inhibition of NF-κB tends to limit injury.4,5 The situation may be even more complex because, in addition to causing injury, NF-κB, particularly the p50 protein, also limits inflammation and plays a key role in resolution of injury during tissue remodeling.6,7 In this issue of JASN, Hussain et al.8 describe the glomerular pathology that develops in mice with a genetically engineered defect in the control of NF-κB activation. Spontaneous glomerular disease occurs within the first 2 wk of life with clear evidence of podocyte injury associated with nuclear translocation of NF-κB. It is not known which of the many potential NF-κB–inducible genes is responsible for podocyte injury; however, there is little doubt that NF-κB activation can cause glomerular injury and any stimulus that activates NF-κB could disrupt podocyte function. This would leave the podocyte very sensitive to any perturbation in its external environment, and such a powerful system as NF-κB needs to be controlled. The podocyte protein nephrin may be part of this control system. Nephrin is a transmembrane protein and a member of the Ig superfamily. It is a vital component of the podocyte slit diaphragm that is involved in maintaining the glomerular filtration barrier. Mutations in the nephrin gene lead to congenital nephrotic syndrome of the Finnish type characterized by heavy proteinuria. Reduced nephrin expression is also seen in other proteinuric glomerular diseases. The extracellular domains of nephrin interact with other nephrin molecules on adjacent foot processes to maintain the structure of the slit diaphragm. Other proteins are present at the junction between adjacent foot processes, forming a protein complex similar to tight adherens junctions. Within this complex, nephrin serves an important signaling function, linking extracellular structures within the slit diaphragm to the actin cytoskeleton.9 This signaling is achieved by its intracellular domain, which contains nine tyrosine residues that interact with several adaptor-signaling proteins. Hussain et al.8 suggest an additional role for nephrin: As a brake on NF-κB signaling. Human podocytes that express mutant nephrin demonstrate increased activation of NF-κB, and this is reversed by restoration of wild-type nephrin expression. The link between nephrin and NF-κB is likely to be complex, but the authors propose one possible link. Nephrin can bind atypical protein kinase C (aPKC), an enzyme that acts as an activator of the NF-κB system. For some reason, the distribution of aPKC is different in podocytes that express wild-type and mutant nephrin. With mutant nephrin, aPKC shows cytoplasmic localization where it can activate pathways leading to IκB degradation. In addition, a dominant negative form of aPKC blocks nephrin-induced suppression of NF-κB activity. These in vitro observations are also consistent with the mouse data. The excessive activation of NF-κB in the mouse model described is due to a deficiency in prostate apoptosis response 4. One function of prostate apoptosis response 4 is to bind and inhibit aPKC, and it is therefore a negative regulator of NF-κB; however, as the authors point out, this may not be the only way in which nephrin and NF-κB interact. This work raises some interesting questions. First, why should nephrin have developed a mechanism to interact with NF-κB signaling pathways? If the model proposed by Hussain et al. is correct, then a stimulus that disrupts the structure of the slit diaphragm will interfere with nephrin function and thereby increase NF-κB activation. This would ultimately lead to a further deterioration in glomerular filtration function and finally overt glomerular disease. An alternative explanation is that the podocyte is using nephrin to sense perturbations in the extracellular space leading to NF-κB–mediated responses that are protective. This leads to the second question: Does NF-κB have a physiologically important role in the maintenance of podocyte structure and function, and, if so, then what is this role? A final possibility is that nephrin represents the physiologic off-switch for NF-κB signaling in the podocyte. When the normal structures of the slit diaphragm and nephrin functions are restored, nephrin would inhibit aPKC activity. This would reduce IκB phosphorylation and degradation, thereby restoring the cytoplasmic localization of inactive NF-κB. The more nephrology learns about podocyte function, the more the divide between proteins of the immune system and epithelial cells narrows. The article by Hussain et al. describes the archetypal transcription factor of the immune system causing injury in an epithelial cell that is controlled by a mechanism unique to a specific cell type within the glomerulus. This follows recent observations that cyclosporine may reduce proteinuria, not by influencing T cell function but by inhibiting calcineurin-dependent dephosphorylation of synaptopodin.10 Synaptopodin is another protein found within junctional complexes in podocytes and has an important role in stabilizing the actin cytoskeleton. These two studies not only provide fascinating insights into podocyte function but also alter the way we look at proteinuric disease and its treatment. Disclosures None.