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

Author

Listed:
  • Ahmed Elwakiel

    (University of Leipzig Medical Center)

  • Dheerendra Gupta

    (University of Leipzig Medical Center)

  • Rajiv Rana

    (University of Leipzig Medical Center)

  • Jayakumar Manoharan

    (University of Leipzig Medical Center)

  • Moh’d Mohanad Al-Dabet

    (University of Leipzig Medical Center
    University of Jordan)

  • Saira Ambreen

    (University of Leipzig Medical Center)

  • Sameen Fatima

    (University of Leipzig Medical Center)

  • Silke Zimmermann

    (University of Leipzig Medical Center)

  • Akash Mathew

    (University of Leipzig Medical Center)

  • Zhiyang Li

    (University of Leipzig Medical Center)

  • Kunal Singh

    (University of Leipzig Medical Center)

  • Anubhuti Gupta

    (University of Leipzig Medical Center)

  • Surinder Pal

    (University of Leipzig Medical Center)

  • Alba Sulaj

    (University of Heidelberg)

  • Stefan Kopf

    (University of Heidelberg)

  • Constantin Schwab

    (University of Heidelberg)

  • Ronny Baber

    (University of Leipzig Medical Center
    Leipzig University)

  • Robert Geffers

    (Helmholtz Centre for Infection Research)

  • Tom Götze

    (Leipzig University)

  • Bekas Alo

    (Leipzig University)

  • Christina Lamers

    (Leipzig University)

  • Paul Kluge

    (Leipzig University)

  • Georg Kuenze

    (Leipzig University
    Leipzig University)

  • Shrey Kohli

    (University of Leipzig Medical Center)

  • Thomas Renné

    (University Medical Center Hamburg-Eppendorf
    Johannes Gutenberg University Medical Center
    Royal College of Surgeons in Ireland)

  • Khurrum Shahzad

    (University of Leipzig Medical Center
    University of the Punjab)

  • Berend Isermann

    (University of Leipzig Medical Center)

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.

Suggested Citation

  • 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 Gu, 2024. "Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52214-8
    DOI: 10.1038/s41467-024-52214-8
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