Gasdermin D-deficient mice are hypersensitive to acute kidney injury

Wulf Tonnus; Francesca Maremonti; Alexia Belavgeni; Markus Latk; Yoshihiro Kusunoki; Anne Brucker; Anne von Mässenhausen; Claudia Meyer; Sophie Locke; Florian Gembardt; Kristina Beer; Paul Hoppenz; Jan U. Becker; Christian Hugo; Hans Joachim Anders; Stefan R. Bornstein; Feng Shao; Andreas Linkermann

doi:10.1038/s41419-022-05230-9

Gasdermin D-deficient mice are hypersensitive to acute kidney injury

Wulf Tonnus, Francesca Maremonti, Alexia Belavgeni, Markus Latk, Yoshihiro Kusunoki, Anne Brucker, Anne von Mässenhausen, Claudia Meyer, Sophie Locke, Florian Gembardt, Kristina Beer, Paul Hoppenz, Jan U. Becker, Christian Hugo, Hans Joachim Anders, Stefan R. Bornstein, Feng Shao, Andreas Linkermann^*

^*Corresponding author for this work

Diabetes

Research output: Contribution to journal › Article › peer-review

37 Citations (Scopus)

Abstract

Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI.

Original language	English
Article number	792
Journal	Cell Death and Disease
Volume	13
Issue number	9
DOIs	https://doi.org/10.1038/s41419-022-05230-9
Publication status	Published - Sept 2022

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Tonnus, W., Maremonti, F., Belavgeni, A., Latk, M., Kusunoki, Y., Brucker, A., von Mässenhausen, A., Meyer, C., Locke, S., Gembardt, F., Beer, K., Hoppenz, P., Becker, J. U., Hugo, C., Anders, H. J., Bornstein, S. R., Shao, F., & Linkermann, A. (2022). Gasdermin D-deficient mice are hypersensitive to acute kidney injury. Cell Death and Disease, 13(9), Article 792. https://doi.org/10.1038/s41419-022-05230-9

@article{32b55ea8de4d4c94809f5e6b3fbdd402,

title = "Gasdermin D-deficient mice are hypersensitive to acute kidney injury",

abstract = "Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI.",

author = "Wulf Tonnus and Francesca Maremonti and Alexia Belavgeni and Markus Latk and Yoshihiro Kusunoki and Anne Brucker and {von M{\"a}ssenhausen}, Anne and Claudia Meyer and Sophie Locke and Florian Gembardt and Kristina Beer and Paul Hoppenz and Becker, {Jan U.} and Christian Hugo and Anders, {Hans Joachim} and Bornstein, {Stefan R.} and Feng Shao and Andreas Linkermann",

note = "Funding Information: Work in the Linkermann Lab is funded by the German Research Foundation (DFG), SFB-TRR 205, SFB-TRR 127, SPP 2306, IRTG 2251, and a Heisenberg-Professorship to AL (project number 324141047). HJA was supported by the Deutsche Forschungsgemeinschaft (AN372/16-2, 27-1, and 30-1) Funding Information: We would like to cordially thank Romy Opitz, Anne Pioch, and C{\'e}line Laqua for expert technical assistance. We thank the Light Microscopy Facility at Dresden BIOTEC, in particular Hella Hartmann, and the histology facility at the CMCB of the TU Dresden with special acknowledgement of Susanne Weiche and Dana Thatmeyer for expert help. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

doi = "10.1038/s41419-022-05230-9",

language = "English",

volume = "13",

journal = "Cell Death and Disease",

issn = "2041-4889",

publisher = "Nature Publishing Group",

number = "9",

}

Tonnus, W, Maremonti, F, Belavgeni, A, Latk, M, Kusunoki, Y, Brucker, A, von Mässenhausen, A, Meyer, C, Locke, S, Gembardt, F, Beer, K, Hoppenz, P, Becker, JU, Hugo, C, Anders, HJ, Bornstein, SR, Shao, F & Linkermann, A 2022, 'Gasdermin D-deficient mice are hypersensitive to acute kidney injury', Cell Death and Disease, vol. 13, no. 9, 792. https://doi.org/10.1038/s41419-022-05230-9

TY - JOUR

T1 - Gasdermin D-deficient mice are hypersensitive to acute kidney injury

AU - Tonnus, Wulf

AU - Maremonti, Francesca

AU - Belavgeni, Alexia

AU - Latk, Markus

AU - Kusunoki, Yoshihiro

AU - Brucker, Anne

AU - von Mässenhausen, Anne

AU - Meyer, Claudia

AU - Locke, Sophie

AU - Gembardt, Florian

AU - Beer, Kristina

AU - Hoppenz, Paul

AU - Becker, Jan U.

AU - Hugo, Christian

AU - Anders, Hans Joachim

AU - Bornstein, Stefan R.

AU - Shao, Feng

AU - Linkermann, Andreas

N1 - Funding Information: Work in the Linkermann Lab is funded by the German Research Foundation (DFG), SFB-TRR 205, SFB-TRR 127, SPP 2306, IRTG 2251, and a Heisenberg-Professorship to AL (project number 324141047). HJA was supported by the Deutsche Forschungsgemeinschaft (AN372/16-2, 27-1, and 30-1) Funding Information: We would like to cordially thank Romy Opitz, Anne Pioch, and Céline Laqua for expert technical assistance. We thank the Light Microscopy Facility at Dresden BIOTEC, in particular Hella Hartmann, and the histology facility at the CMCB of the TU Dresden with special acknowledgement of Susanne Weiche and Dana Thatmeyer for expert help. Publisher Copyright: © 2022, The Author(s).

PY - 2022/9

Y1 - 2022/9

N2 - Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI.

AB - Signaling pathways of regulated necrosis, such as necroptosis and ferroptosis, contribute to acute kidney injury (AKI), but the role of pyroptosis is unclear. Pyroptosis is mediated by the pore-forming protein gasdermin D (GSDMD). Here, we report a specific pattern of GSDMD-protein expression in the peritubular compartment of mice that underwent bilateral ischemia and reperfusion injury (IRI). Along similar lines, the GSDMD-protein expression in whole kidney lysates increased during the first 84 h following cisplatin-induced AKI. Importantly, unlike whole kidney lysates, no GSDMD-protein expression was detectable in isolated kidney tubules. In IRI and cisplatin-induced AKI, GSDMD-deficient mice exhibited hypersensitivity to injury as assessed by tubular damage, elevated markers of serum urea, and serum creatinine. This hypersensitivity was reversed by a combined deficiency of GSDMD and the necroptosis mediator mixed lineage kinase domain-like (MLKL). In conclusion, we demonstrate a non-cell autonomous role for GSDMD in protecting the tubular compartment from necroptosis-mediated damage in IRI.

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U2 - 10.1038/s41419-022-05230-9

DO - 10.1038/s41419-022-05230-9

M3 - Article

C2 - 36109515

AN - SCOPUS:85137906361

SN - 2041-4889

VL - 13

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 9

M1 - 792

ER -

Gasdermin D-deficient mice are hypersensitive to acute kidney injury

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