Circulating CASK is associated with recurrent focal segmental glomerulosclerosis after transplantation

PLoS One. 2019 Jul 29;14(7):e0219353. doi: 10.1371/journal.pone.0219353. eCollection 2019.

Abstract

Introduction: Focal and Segmental GlomeruloSclerosis (FSGS) can cause nephrotic syndrome with a risk of progression to end-stage renal disease. The idiopathic form has a high rate of recurrence after transplantation, suggesting the presence of a systemic circulating factor that causes glomerular permeability and can be removed by plasmapheresis or protein-A immunoadsorption.

Results: To identify this circulating factor, the eluate proteins bound on therapeutic immunoadsorption with protein-A columns were analyzed by comparative electrophoresis and mass spectrometry. A soluble form of calcium/calmodulin-dependent serine protein kinase (CASK) was identified. CASK was immunoprecipitated only in the sera of patients with recurrent FSGS after transplantation and not in control patients. Recombinant-CASK (rCASK) induced the reorganization of the actin cytoskeleton in immortalized podocytes, a redistribution of synaptopodin, ZO-1,vinculin and ENA. rCASK also induced alterations in the permeability of a monolayer of podocytes and increased the motility of pdodocytes in vitro. The extracellular domain of CD98, a transmembrane receptor expressed on renal epithelial cells, has been found to co-immunoprecipitated with rCASK. The invalidation of CD98 with siRNA avoided the structural changes of rCask treated cells suggesting its involvement in physiopathology of the disease. In mice, recombinant CASK induced proteinuria and foot process effacement in podocytes.

Conclusion: Our results suggest that CASK can induce the recurrence of FSGS after renal transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cells, Cultured
  • Cytoskeleton / metabolism
  • Cytoskeleton / ultrastructure
  • Female
  • Fusion Regulatory Protein-1 / metabolism
  • Glomerulosclerosis, Focal Segmental / blood*
  • Glomerulosclerosis, Focal Segmental / complications
  • Guanylate Kinases / blood*
  • Humans
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / ultrastructure
  • Kidney Transplantation*
  • Male
  • Membranes / metabolism
  • Membranes / ultrastructure
  • Mice
  • Middle Aged
  • Podocytes / metabolism
  • Podocytes / pathology
  • Podocytes / ultrastructure
  • Protein Binding
  • Proteinuria / complications
  • Recurrence

Substances

  • Fusion Regulatory Protein-1
  • CASK kinases
  • Guanylate Kinases

Grants and funding

HKL and AD were supported by “Association des Malades d’un Syndrome Néphrotique” (France), the “Fondation pour la Recherche Médicale”, “Fondation du Rein” (France), the “Fondation Serge Dassault” (France) the “Agence de la Biomedicine” (France) and INSERM-transfert (France). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.