Factor XII signaling via uPAR-integrin beta1 axis promotes tubular senescence in diabetic kidney disease

Coagulation FXII, known for its role in activation of hemostasis and inflammation, plays a hemostasis-independent role in several inflammatory and fibrotic diseases. The causal role of FXII in the pathophysiology of DKD in unknown. Using a combination of unbiased approaches, diabetes models, analyses of human samples, computational modeling, and in vitro studies, we identified a role of zymogen FXII signaling in the progression of DKD. We here show that the zymogen FXII binds to uPAR and integrin beta1 on tubular cells, promoting DNA damage and senescence. Targeting FXII or its interaction with uPAR may represent promising therapeutic avenues for DKD.