Nephrin deficiency activates NF-kappaB and promotes glomerular injury.

Increasing evidence implicates activation of NF-kappaB in a variety of glomerular diseases, but the mechanisms involved are unknown. Here, upregulation of NF-kappaB in the podocytes of transgenic mice resulted in glomerulosclerosis and proteinuria. Absence of the podocyte protein nephrin resulted in NF-kappaB activation, suggesting that nephrin negatively regulates the NF-kappaB pathway. Signal transduction assays supported a functional relationship between nephrin and NF-kappaB and suggested the involvement of atypical protein kinase C (aPKCzeta/lambda/iota) as an intermediary. We propose that disruption of the slit diaphragm leads to activation of NF-kappaB; subsequent upregulation of NF-kappaB-driven genes results in glomerular damage mediated by NF-kappaB-dependent pathways. In summary, nephrin may normally limit NF-kappaB activity in the podocyte, suggesting a mechanism by which it might discourage the evolution of glomerular disease.

[1]  Kwanghee Kim,et al.  The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A , 2008, Nature Medicine.

[2]  Bernhard Schermer,et al.  Neph-Nephrin Proteins Bind the Par3-Par6-Atypical Protein Kinase C (aPKC) Complex to Regulate Podocyte Cell Polarity* , 2008, Journal of Biological Chemistry.

[3]  E. Bock,et al.  TLR4 links podocytes with the innate immune system to mediate glomerular injury. , 2008, Journal of the American Society of Nephrology : JASN.

[4]  Thamara K. Dayarathna,et al.  Phosphorylated YDXV Motifs and Nck SH2/SH3 Adaptors Act Cooperatively To Induce Actin Reorganization , 2008, Molecular and Cellular Biology.

[5]  P. Dentelli,et al.  The monocyte chemoattractant protein-1/cognate CC chemokine receptor 2 system affects cell motility in cultured human podocytes. , 2007, The American journal of pathology.

[6]  Andre Levchenko,et al.  A homeostatic model of IκB metabolism to control constitutive NF-κB activity , 2007, Molecular systems biology.

[7]  M. Peifer,et al.  aPKC controls microtubule organization to balance adherens junction symmetry and planar polarity during development. , 2007, Developmental cell.

[8]  T. Roger,et al.  Differential Regulation of Toll-Like Receptor 4 Gene Expression in Renal Cells by Angiotensin II: Dependency on AP1 and PU.1 Transcriptional Sites , 2007, American Journal of Nephrology.

[9]  J. Tavaré,et al.  Nephrin Is Critical for the Action of Insulin on Human Glomerular Podocytes , 2007, Diabetes.

[10]  P. Gerke,et al.  β-Arrestin2 mediates nephrin endocytosis and impairs slit diaphragm integrity , 2006, Proceedings of the National Academy of Sciences.

[11]  L. Espinosa,et al.  Efficient nuclear export of p65-IκBα complexes requires 14-3-3 proteins , 2006, Journal of Cell Science.

[12]  J. Hubbell,et al.  Activation of cell-survival transcription factor NFkappaB in L1Ig6-stimulated endothelial cells. , 2006, Journal of biomedical materials research. Part A.

[13]  L. Holzman,et al.  Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. , 2006, The Journal of clinical investigation.

[14]  T. Luedde,et al.  Dissection of the NF-κB signalling cascade in transgenic and knockout mice , 2006, Cell Death and Differentiation.

[15]  M. Diaz-Meco,et al.  PKCζ at the crossroad of NF-κB and Jak1/Stat6 signaling pathways , 2006, Cell Death and Differentiation.

[16]  K. Wagner,et al.  An Inducible Mouse Model for PAX2-Dependent Glomerular Disease: Insights into a Complex Pathogenesis , 2006, Current Biology.

[17]  Tony Pawson,et al.  Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes , 2006, Nature.

[18]  A. Hoffmann,et al.  Circuitry of nuclear factor κB signaling , 2006 .

[19]  Scott Martinka,et al.  Persistent NF-κB activation in renal epithelial cells in a mouse model of HIV-associated nephropathy , 2006 .

[20]  R. Sinniah,et al.  In situ glomerular expression of activated NF-κB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy , 2006, Virchows Archiv.

[21]  Huilin Zhou,et al.  Cell junction-associated proteins IQGAP1, MAGI-2, CASK, spectrins, and alpha-actinin are components of the nephrin multiprotein complex. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Leroy,et al.  A role for PKCζ in the LPS-induced translocation NF-κB p65 subunit in cultured myometrial cells , 2005 .

[23]  H. Kawachi,et al.  SRC-family kinase Fyn phosphorylates the cytoplasmic domain of nephrin and modulates its interaction with podocin. , 2004, Journal of the American Society of Nephrology : JASN.

[24]  Eetu Mäkelä,et al.  Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography. , 2004, The Journal of clinical investigation.

[25]  Sankar Ghosh,et al.  Signaling to NF-kappaB. , 2004, Genes & development.

[26]  R. Kalluri,et al.  Induction of B7-1 in podocytes is associated with nephrotic syndrome. , 2004, The Journal of clinical investigation.

[27]  M. Daha,et al.  Mechanism of steroid action in renal epithelial cells. , 2004, Kidney international.

[28]  Csaba Szabo,et al.  Disruption of the actin cytoskeleton results in nuclear factor‐κB activation and inflammatory mediator production in cultured human intestinal epithelial cells , 2004 .

[29]  M. Mclaughlin,et al.  Complement mediates nephrin redistribution and actin dissociation in experimental membranous nephropathy. , 2003, Kidney international.

[30]  J. Egido,et al.  Effect of simultaneous blockade of AT1 and AT2 receptors on the NFkappaB pathway and renal inflammatory response. , 2003, Kidney international. Supplement.

[31]  Pilar Martín,et al.  Regulation of mature T lymphocyte proliferation and differentiation by Par‐4 , 2003, The EMBO journal.

[32]  K. Tryggvason,et al.  Clustering-induced tyrosine phosphorylation of nephrin by Src family kinases. , 2003, Kidney international.

[33]  A. Durán,et al.  Essential role of RelA Ser311 phosphorylation by ζPKC in NF‐κB transcriptional activation , 2003 .

[34]  Bernhard Schermer,et al.  Nephrin and CD2AP Associate with Phosphoinositide 3-OH Kinase and Stimulate AKT-Dependent Signaling , 2003, Molecular and Cellular Biology.

[35]  L. Holzman,et al.  Fyn Binds to and Phosphorylates the Kidney Slit Diaphragm Component Nephrin* , 2003, Journal of Biological Chemistry.

[36]  S. Saccani,et al.  Modulation of NF-κB Activity by Exchange of Dimers , 2003 .

[37]  J. Moscat,et al.  NF‐κB activation by protein kinase C isoforms and B‐cell function , 2003 .

[38]  T. B. Huber,et al.  NEPH1 defines a novel family of podocin‐interacting proteins , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  S. Shankland,et al.  Podocyte biology and response to injury. , 2002, Journal of the American Society of Nephrology : JASN.

[40]  S. Ito,et al.  Significance of early phenotypic change of glomerular podocytes detected by Pax2 in primary focal segmental glomerulosclerosis. , 2002, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[41]  M. O'hare,et al.  A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. , 2002, Journal of the American Society of Nephrology : JASN.

[42]  P. Scambler,et al.  Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. , 2002, Human molecular genetics.

[43]  M. Saleem,et al.  Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. , 2001, The Journal of clinical investigation.

[44]  T. Benzing,et al.  Interaction with Podocin Facilitates Nephrin Signaling* , 2001, The Journal of Biological Chemistry.

[45]  T. Takano,et al.  Complement C5b-9 induces cyclooxygenase-2 gene transcription in glomerular epithelial cells. , 2001, American journal of physiology. Renal physiology.

[46]  Juan F. García,et al.  Targeted Disruption of the ζPKC Gene Results in the Impairment of the NF-κB Pathway , 2001 .

[47]  S. Silbernagl,et al.  Albumin in the mg/l-range activates NF-kappaB in renal proximal tubule-derived cell lines via tyrosine kinases and protein kinase C. , 2001, European journal of medical research.

[48]  G. Camussi,et al.  Nephrin redistribution on podocytes is a potential mechanism for proteinuria in patients with primary acquired nephrotic syndrome. , 2001, The American journal of pathology.

[49]  Corinne Antignac,et al.  NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome , 2000, Nature Genetics.

[50]  H. Pahl.  Activators and target genes of Rel/NF-κB transcription factors , 1999, Oncogene.

[51]  Michael Loran Dustin,et al.  Congenital nephrotic syndrome in mice lacking CD2-associated protein. , 1999, Science.

[52]  M. Diaz-Meco,et al.  Inactivation of the Inhibitory κB Protein Kinase/Nuclear Factor κB Pathway by Par-4 Expression Potentiates Tumor Necrosis Factor α-induced Apoptosis* , 1999, The Journal of Biological Chemistry.

[53]  K. Lemley,et al.  The role of the podocyte in glomerulosclerosis. , 1999, Current opinion in nephrology and hypertension.

[54]  M. Diaz-Meco,et al.  The interaction of p62 with RIP links the atypical PKCs to NF‐κB activation , 1999, The EMBO journal.

[55]  G. Bren,et al.  Activation of IκB Kinase β by Protein Kinase C Isoforms , 1999, Molecular and Cellular Biology.

[56]  H. Grunicke,et al.  Evidence That Atypical Protein Kinase C-λ and Atypical Protein Kinase C-ζ Participate in Ras-mediated Reorganization of the F-actin Cytoskeleton , 1999, The Journal of cell biology.

[57]  P. Graves,et al.  14-3-3 Proteins Are Required for Maintenance of Raf-1 Phosphorylation and Kinase Activity , 1998, Molecular and Cellular Biology.

[58]  L Peltonen,et al.  Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome. , 1998, Molecular cell.

[59]  Z. Cao,et al.  MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. , 1997, Immunity.

[60]  E. Zandi,et al.  The IκB Kinase Complex (IKK) Contains Two Kinase Subunits, IKKα and IKKβ, Necessary for IκB Phosphorylation and NF-κB Activation , 1997, Cell.

[61]  J. Licht,et al.  A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1 , 1996, Molecular and cellular biology.

[62]  M. Diaz-Meco,et al.  The Product of par-4, a Gene Induced during Apoptosis, Interacts Selectively with the Atypical Isoforms of Protein Kinase C , 1996, Cell.

[63]  B. Ryffel,et al.  Lipopolysaccharide-induced glomerulonephritis develops in the absence of interferon-gamma signaling. , 1996, Experimental nephrology.

[64]  Lozano,et al.  A dominant negative protein kinase C zeta subspecies blocks NF-kappa B activation , 1993, Molecular and cellular biology.

[65]  W. Greene,et al.  The 65-kDa subunit of human NF-kappa B functions as a potent transcriptional activator and a target for v-Rel-mediated repression. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[66]  Jun Xie,et al.  Par-4 is a novel mediator of renal tubule cell death in models of ischemia-reperfusion injury. , 2007, American journal of physiology. Renal physiology.

[67]  J. Vieira,et al.  Chronic inhibition of nuclear factor-kappaB attenuates renal injury in the 5/6 renal ablation model. , 2007, American journal of physiology. Renal physiology.

[68]  L. Krushel,et al.  NF‐κB activation by N‐CAM and cytokines in astrocytes is regulated by multiple protein kinases and redox modulation , 2001, Glia.

[69]  M. Gubler,et al.  WT1 and PAX-2 podocyte expression in Denys-Drash syndrome and isolated diffuse mesangial sclerosis. , 1999, The American journal of pathology.

[70]  J. Lamerdin,et al.  Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations. , 1999, American journal of human genetics.