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

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 kidne...

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Main Authors: Elwakiel, Ahmed (Author) , Gupta, Dheerendra (Author) , Rana, Rajiv (Author) , Manoharan, Jayakumar (Author) , Al-Dabet, Moh’d Mohanad (Author) , Ambreen, Saira (Author) , Fatima, Sameen (Author) , Zimmermann, Silke (Author) , Mathew, Akash (Author) , Li, Zhiyang (Author) , Singh, Kunal (Author) , Gupta, Anubhuti (Author) , Pal, Surinder (Author) , Sulaj, Alba (Author) , Kopf, Stefan (Author) , Schwab, Constantin (Author) , Baber, Ronny (Author) , Geffers, Robert (Author) , Götze, Tom (Author) , Alo, Bekas (Author) , Lamers, Christina (Author) , Kluge, Paul (Author) , Künze, Georg (Author) , Kohli, Shrey (Author) , Renné, Thomas (Author) , Shahzad Hussain, Khurrum (Author) , Isermann, Berend (Author)
Format: Article (Journal)
Language:English
Published: 11 September 2024
In: Nature Communications
Year: 2024, Volume: 15, Pages: 1-20
ISSN:2041-1723
DOI:10.1038/s41467-024-52214-8
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-024-52214-8
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-024-52214-8
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Author Notes: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 and Berend Isermann
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Summary: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.
Item Description:Gesehen am 03.06.2025
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-024-52214-8

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