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.

凝血因子XII（Coagulation FXII）因其在止血与炎症激活中的作用而为人熟知，但其在多种炎症及纤维化疾病中可发挥不依赖于止血功能的作用。目前，FXII在糖尿病肾病（Diabetic Kidney Disease, DKD）病理生理进程中的因果作用仍未明确。本研究联合运用无偏倚研究方法（unbiased approaches）、糖尿病动物模型、人体样本分析、计算建模与体外实验，明确了酶原FXII（zymogen FXII）信号通路在DKD进展中的作用。研究证实，酶原FXII可结合肾小管细胞表面的尿激酶型纤溶酶原激活物受体（urokinase-type plasminogen activator receptor, uPAR）与整合素β1（integrin beta1），进而促进DNA损伤与细胞衰老。靶向FXII或其与uPAR的相互作用，或可成为DKD极具潜力的治疗途径。