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 and Berend Isermann ()
Additional contact information
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
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
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
Shrey Kohli: University of Leipzig Medical Center
Thomas Renné: University Medical Center Hamburg-Eppendorf
Khurrum Shahzad: University of Leipzig Medical Center
Berend Isermann: University of Leipzig Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52214-8

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