ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage

J Am Soc Nephrol. 2021 Jun 1;32(6):1389-1408. doi: 10.1681/ASN.2020081213. Epub 2021 Mar 30.


Background: Podocytes embrace the glomerular capillaries with foot processes, which are interconnected by a specialized adherens junction to ultimately form the filtration barrier. Altered adhesion and loss are common features of podocyte injury, which could be mediated by shedding of cell-adhesion molecules through the regulated activity of cell surface-expressed proteases. A Disintegrin and Metalloproteinase 10 (ADAM10) is such a protease known to mediate ectodomain shedding of adhesion molecules, among others. Here we evaluate the involvement of ADAM10 in the process of antibody-induced podocyte injury.

Methods: Membrane proteomics, immunoblotting, high-resolution microscopy, and immunogold electron microscopy were used to analyze human and murine podocyte ADAM10 expression in health and kidney injury. The functionality of ADAM10 ectodomain shedding for podocyte development and injury was analyzed, in vitro and in vivo, in the anti-podocyte nephritis (APN) model in podocyte-specific, ADAM10-deficient mice.

Results: ADAM10 is selectively localized at foot processes of murine podocytes and its expression is dispensable for podocyte development. Podocyte ADAM10 expression is induced in the setting of antibody-mediated injury in humans and mice. Podocyte ADAM10 deficiency attenuates the clinical course of APN and preserves the morphologic integrity of podocytes, despite subepithelial immune-deposit formation. Functionally, ADAM10-related ectodomain shedding results in cleavage of the cell-adhesion proteins N- and P-cadherin, thus decreasing their injury-related surface levels. This favors podocyte loss and the activation of downstream signaling events through the Wnt signaling pathway in an ADAM10-dependent manner.

Conclusions: ADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury.

Keywords: glomerular disease; membranous nephropathy; podocyte; proteinuria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / genetics
  • ADAM10 Protein / metabolism*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Autoantibodies / adverse effects
  • Blood Urea Nitrogen
  • Cadherins / metabolism
  • Cell Adhesion
  • Cell Communication
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Creatinine / urine
  • Disease Models, Animal
  • Female
  • Glomerular Filtration Barrier / pathology
  • Glomerular Filtration Barrier / physiopathology
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nephritis / metabolism*
  • Nephritis / pathology
  • Nephrotic Syndrome / metabolism*
  • Nephrotic Syndrome / pathology
  • Podocytes / metabolism*
  • Podocytes / pathology*
  • Podocytes / physiology
  • Proteomics
  • Renal Insufficiency, Chronic / metabolism*
  • Tissue Array Analysis
  • Transcriptome
  • Wnt Signaling Pathway


  • Autoantibodies
  • Cadherins
  • Membrane Proteins
  • Creatinine
  • Amyloid Precursor Protein Secretases
  • ADAM10 Protein
  • ADAM10 protein, human
  • Adam10 protein, mouse