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

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ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage. / Sachs, Marlies; Wetzel, Sebastian; Reichelt, Julia; Sachs, Wiebke; Schebsdat, Lisa; Zielinski, Stephanie; Seipold, Lisa; Heintz, Lukas; Müller, Stephan A; Kretz, Oliver; Lindenmeyer, Maja; Wiech, Thorsten; Huber, Tobias B; Lüllmann-Rauch, Renate; Lichtenthaler, Stefan F; Saftig, Paul; Meyer-Schwesinger, Catherine.

In: J AM SOC NEPHROL, Vol. 32, No. 6, 01.06.2021, p. 1389-1408.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sachs, M, Wetzel, S, Reichelt, J, Sachs, W, Schebsdat, L, Zielinski, S, Seipold, L, Heintz, L, Müller, SA, Kretz, O, Lindenmeyer, M, Wiech, T, Huber, TB, Lüllmann-Rauch, R, Lichtenthaler, SF, Saftig, P & Meyer-Schwesinger, C 2021, 'ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage', J AM SOC NEPHROL, vol. 32, no. 6, pp. 1389-1408. https://doi.org/10.1681/ASN.2020081213

APA

Sachs, M., Wetzel, S., Reichelt, J., Sachs, W., Schebsdat, L., Zielinski, S., Seipold, L., Heintz, L., Müller, S. A., Kretz, O., Lindenmeyer, M., Wiech, T., Huber, T. B., Lüllmann-Rauch, R., Lichtenthaler, S. F., Saftig, P., & Meyer-Schwesinger, C. (2021). ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage. J AM SOC NEPHROL, 32(6), 1389-1408. https://doi.org/10.1681/ASN.2020081213

Vancouver

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. 2021 Jun 1;32(6):1389-1408. https://doi.org/10.1681/ASN.2020081213

Bibtex

@article{a200d196dcb34402add13da8746c72c0,
title = "ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage",
abstract = "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.",
author = "Marlies Sachs and Sebastian Wetzel and Julia Reichelt and Wiebke Sachs and Lisa Schebsdat and Stephanie Zielinski and Lisa Seipold and Lukas Heintz and M{\"u}ller, {Stephan A} and Oliver Kretz and Maja Lindenmeyer and Thorsten Wiech and Huber, {Tobias B} and Renate L{\"u}llmann-Rauch and Lichtenthaler, {Stefan F} and Paul Saftig and Catherine Meyer-Schwesinger",
note = "Copyright {\textcopyright} 2021 by the American Society of Nephrology.",
year = "2021",
month = jun,
day = "1",
doi = "10.1681/ASN.2020081213",
language = "English",
volume = "32",
pages = "1389--1408",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "6",

}

RIS

TY - JOUR

T1 - ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage

AU - Sachs, Marlies

AU - Wetzel, Sebastian

AU - Reichelt, Julia

AU - Sachs, Wiebke

AU - Schebsdat, Lisa

AU - Zielinski, Stephanie

AU - Seipold, Lisa

AU - Heintz, Lukas

AU - Müller, Stephan A

AU - Kretz, Oliver

AU - Lindenmeyer, Maja

AU - Wiech, Thorsten

AU - Huber, Tobias B

AU - Lüllmann-Rauch, Renate

AU - Lichtenthaler, Stefan F

AU - Saftig, Paul

AU - Meyer-Schwesinger, Catherine

N1 - Copyright © 2021 by the American Society of Nephrology.

PY - 2021/6/1

Y1 - 2021/6/1

N2 - 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.

AB - 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.

U2 - 10.1681/ASN.2020081213

DO - 10.1681/ASN.2020081213

M3 - SCORING: Journal article

C2 - 33785583

VL - 32

SP - 1389

EP - 1408

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 6

ER -