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

Abstract

BackgroundPodocytes 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.MethodsMembrane 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.ResultsADAM10 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.ConclusionsADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury.

Low circulating miR-190a-5p predicts progression of chronic kidney disease.

“…5A). One of the most signi cantly negatively correlated target genes of miR-190a-5p was Adam10 (p = 0.004), which is a sheddase and has been shown to mediate kidney in pre-clinical models (35). Adam10 expression was signi cantly increased in bulk cortical kidney during ureteric obstruction in our murine model as would be expected following loss of miR-190a-5p repression (Fig.…”

“…We demonstrate that ADAM10 expression changes conversely to the expression of miR-190a-5p in human renal proximal tubule cells suggesting that it is a target of miR-190-5p. It is possible that miR-190a-5p may maintain kidney cell health by inhibiting ADAM10 activity as Adam10 knockout protects against kidney injury (35). ADAM10 promotes shedding of ectodomains of cell surface adhesion molecules such as cadherins which are important in maintaining the integrity of the epithelial cell monolayer (35).…”

Low circulating miR-190a-5p predicts progression of chronic kidney disease.

“…5A). One of the most signi cantly negatively correlated target genes of miR-190a-5p was Adam10 (p = 0.004), which is a sheddase and has been shown to mediate kidney injury in pre-clinical models (35). Adam10 expression was signi cantly increased in bulk cortical kidney during ureteric obstruction in our murine model as would be expected following loss of miR-190a-5p repression (Fig.…”

Identification of Hub Genes and Immune-Related Pathways for Membranous Nephropathy by Bioinformatics Analysis

“…In MN, substantial changes in the expression levels and distribution of vinculin were observed, which is a cytoplasmic protein that binds actin filaments to integrin-mediated cell-matrix adhesion and cadherin-based intercellular junctions (Lausecker et al, 2018). In addition, Disintegrin and Metalloproteinase 10 (ADAM10) in MN, a protease, is upregulated in inflammatory environment and mediates the shedding of extracellular domain of injury-associated cadherins leading to podocyte damage (Sachs et al, 2021). Also, serum containing PLA2R antibodies inhibited podocytes' capacity to adhere to type IV collagen in vitro, providing evidence that serum soluble pathogenic factors disrupt podocyte adhesion in MN (Skoberne et al, 2014).…”