On the cover: A common feature of injury-related podocyte loss is the modification of the interconnecting slit membrane. In the present study, the authors exploit the involvement of the regulated activity of the cell surface expressed A Disintegrin and Metalloproteinase 10 (ADAM10, blue) in this process, as cell-cell adhesion proteins such as cadherins (green) are among the known ADAM10 substrates. The image summarizes the findings of the study. ADAM10 is specifically expressed at foot processes and dispensable for glomerular development (upper panel). Podocyte injury (middle panel) is induced by anti-podocyte antibodies (red) resulting in proteinuria (yellow circles) and podocyte detachment through cleavage of injury-induced cadherins resulting in Wnt signaling. The podocyte-specific deletion of ADAM10 (last panel) protects from ADAM10-mediated ectodomain shedding of injury-related cadherins, thereby stabilizing the slit membrane. Decreased protein and podocyte loss are the result.

Reference: Sachs M, Wetzel S, Reichelt J, Sachs W, Schebsdat L, Zielinski S, et al.: ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage. J Am Soc Nephrol 32: 1389–1408, 2021

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