Pdlim2 is a novel actin-regulating protein of podocyte foot processes

Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Kidney International (Impact Factor: 8.56). 08/2011; 80(10):1045-54. DOI: 10.1038/ki.2011.231
Source: PubMed


The slit diaphragm and the apical and basal membrane domains of podocytes are connected to each other by an actin-based cytoskeleton critical to the maintenance of the glomerular filtration barrier. In an effort to discover novel regulatory proteins of the podocyte foot process, we identified and characterized pdlim2, a member of the actin-associated LIM protein subfamily of cytosolic proteins typified by an N-terminal PDZ domain and a C-terminal LIM domain. In the kidney, the pdlim2 protein is highly specific for the glomerulus and podocyte foot processes as shown by RT-PCR, western blotting, immunofluorescence, and immunoelectron microscopy. In cultured podocytes, pdlim2 was associated with stress fibers and cortical actin. Pdlim2 seems to regulate actin dynamics in podocytes since stress fibers were stabilized in its presence. Mechanistically, pdlim2 interacts with two actin-associated podocyte proteins, α-actinin-4 and angiomotin-like-1, as shown by immunoprecipitation and yeast two-hybrid analyses. By semi-quantitative immunoelectron microscopy, there was a reduced expression of pdlim2 in podocytes of patients with minimal change nephrotic syndrome and membranous nephropathy, whereas its expression was unchanged in patients with focal segmental glomerulosclerosis. Hence, pdlim2 is a novel actin-regulating protein of podocyte foot processes that may have a role in the pathogenesis of glomerular diseases.

1 Follower
14 Reads
  • Source
    • "To analyze protein-protein interactions of dendrin, we performed a yeast two-hybrid screen. To identify meaningful interactions occurring in the podocyte, we used our own glomerular cDNA library [16] as a prey-library. The screening fished out 15 candidate proteins (Table 1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glomerular podocyte cells are critical for the function of the renal ultrafiltration barrier. Especially, the highly specialized cell-cell junction of podocytes, the slit diaphragm, has a central role in the filtration barrier. This is highlighted by the fact that mutations in molecular components of the slit diaphragm, including nephrin and Cd2-associated protein (Cd2ap), result in proteinuric diseases in man. Dendrin is a poorly characterized cytosolic component of the slit diaphragm in where it interacts with nephrin and Cd2ap. Dendrin is highly specific for the podocyte slit diaphragm, suggesting that it has a dedicated role in the glomerular filtration barrier. In this study, we have generated a dendrin knockout mouse line and explored the molecular interactions of dendrin. Dendrin-deficient mice were viable, fertile, and had a normal life span. Morphologically, the glomerulogenesis proceeded normally and adult dendrin-deficient mice showed normal glomerular histology. No significant proteinuria was observed. Following glomerular injury, lack of dendrin did not affect the severity of the damage or the recovery process. Yeast two-hybrid screen and co-immunoprecipitation experiments showed that dendrin binds to Wt1-interacting protein (Wtip) and growth arrest and DNA-damage-inducible 45 alpha (Gadd45a). Wtip and Gadd45a mediate gene transcription in the nucleus, suggesting that dendrin may have similar functions in podocytes. In line with this, we observed the relocation of dendrin to nucleus in adriamycin nephropathy model. Our results indicate that dendrin is dispensable for the function of the normal glomerular filtration barrier and that dendrin interacts with Wtip and Gadd45a.
    PLoS ONE 12/2013; 8(12):e83133. DOI:10.1371/journal.pone.0083133 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genetically modified immune responses to infections and self-antigens initiate most forms of GN by generating pathogen- and danger-associated molecular patterns that stimulate Toll-like receptors and complement. These innate immune responses activate circulating monocytes and resident glomerular cells to release inflammatory mediators and initiate adaptive, antigen-specific immune responses that collectively damage glomerular structures. CD4 T cells are needed for B cell-driven antibody production that leads to immune complex formation in glomeruli, complement activation, and injury induced by both circulating inflammatory and resident glomerular effector cells. Th17 cells can also induce glomerular injury directly. In this review, information derived from studies in vitro, well characterized experimental models, and humans summarize and update likely pathogenic mechanisms involved in human diseases presenting as nephritis (postinfectious GN, IgA nephropathy, antiglomerular basement membrane and antineutrophil cytoplasmic antibody-mediated crescentic GN, lupus nephritis, type I membranoproliferative GN), and nephrotic syndrome (minimal change/FSGS, membranous nephropathy, and C3 glomerulopathies). Advances in understanding the immunopathogenesis of each of these entities offer many opportunities for future therapeutic interventions.
    Journal of the American Society of Nephrology 03/2012; 23(3):381-99. DOI:10.1681/ASN.2011030304 · 9.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: De novo membranous nephropathy (MN) is an uncommon complication of kidney transplantation, which shows histological findings similar to those seen in recurrent MN, but with some distinct differences. The clinical presentation may be variable, from asymptomatic to nephrotic proteinuria. The disease may run an indolent course or may have an accelerated course leading to allograft loss. De novo membranous nephropathy (MN) can develop in transplant recipients with viral hepatitis, Alport syndrome, ureteral obstruction, renal infarction, or in conjunction with recurrent IgA nephritis. Histologic signs of allograft rejection are often associated with or can antedate de novo MN. These findings suggest that donor-specific antibodies and antibody-mediated rejection might play a pathogenetic role in some patients with de novo MN. However, signs of rejection were absent in a number of cases, and in some instances the disease developed in recipients of "full house" HLA- matched kidneys. Thus, it seems possible that de novo MN is not because of allograft rejection per se, but is triggered by different injuries that can create an inflammatory environment, activate innate immunity, and expose hidden (cryptic) antigens, probably different from those observed to be involved in idiopathic MN. These events can lead to the production of circulating antibodies and in situ formation of immune complexes (IC) and the morphological lesion of MN.
    Transplant International 08/2012; 25(12). DOI:10.1111/j.1432-2277.2012.01548.x · 2.60 Impact Factor
Show more