Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease

Ahmed Elwakiel; Dheerendra Gupta; Rajiv Rana; Jayakumar Manoharan; Moh’d Mohanad Al-Dabet; Saira Ambreen; Sameen Fatima; Silke Zimmermann; Akash Mathew; Zhiyang Li; Kunal Singh; Anubhuti Gupta; Surinder Pal; Alba Sulaj; Stefan Kopf; Constantin Schwab; Ronny Baber; Robert Geffers; Tom Götze; Bekas Alo; Christina Lamers; Paul Kluge; Georg Kuenze; Shrey Kohli; Thomas Renné; Khurrum Shahzad; Berend Isermann

doi:10.1038/s41467-024-52214-8

Nature Communications (Sep 2024)

Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease

Ahmed Elwakiel,
Dheerendra Gupta,
Rajiv Rana,
Jayakumar Manoharan,
Moh’d Mohanad Al-Dabet,
Saira Ambreen,
Sameen Fatima,
Silke Zimmermann,
Akash Mathew,
Zhiyang Li,
Kunal Singh,
Anubhuti Gupta,
Surinder Pal,
Alba Sulaj,
Stefan Kopf,
Constantin Schwab,
Ronny Baber,
Robert Geffers,
Tom Götze,
Bekas Alo,
Christina Lamers,
Paul Kluge,
Georg Kuenze,
Shrey Kohli,
Thomas Renné,
Khurrum Shahzad,
Berend Isermann

Affiliations

Ahmed Elwakiel: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Dheerendra Gupta: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Rajiv Rana: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Jayakumar Manoharan: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Moh’d Mohanad Al-Dabet: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Saira Ambreen: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Sameen Fatima: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Silke Zimmermann: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Akash Mathew: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Zhiyang Li: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Kunal Singh: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Anubhuti Gupta: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Surinder Pal: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Alba Sulaj: Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg
Stefan Kopf: Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg
Constantin Schwab: Institute of pathology, University of Heidelberg
Ronny Baber: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Robert Geffers: Genome Analytics, Helmholtz Centre for Infection Research
Tom Götze: Institute for Drug Discovery, Faculty of Medicine, Leipzig University
Bekas Alo: Institute for Drug Discovery, Faculty of Medicine, Leipzig University
Christina Lamers: Institute for Drug Discovery, Faculty of Medicine, Leipzig University
Paul Kluge: Institute for Drug Discovery, Faculty of Medicine, Leipzig University
Georg Kuenze: Institute for Drug Discovery, Faculty of Medicine, Leipzig University
Shrey Kohli: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Thomas Renné: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
Khurrum Shahzad: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center
Berend Isermann: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center

DOI: https://doi.org/10.1038/s41467-024-52214-8
Journal volume & issue: Vol. 15, no. 1
pp. 1 – 20

Abstract

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Abstract Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12 -/- ) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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