Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Sci Transl Med. 2017 Nov 22;9(417). doi: 10.1126/scitranslmed.aam8475.
Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute-specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box-containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute-AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.
慢性肾脏病（CKD/尿毒症）仍然令人困扰，因为它会增加动脉血栓形成的风险，并且与标准抗血栓/抗血小板治疗相关的出血并发症也有关联。虽然吲哚尿溶质和血管壁蛋白（如组织因子（TF）和芳烃受体（AHR））的相关性正在被定义，但驱动血栓形成和出血风险的具体机制尚未完全了解。我们现在提出了一种吲哚溶质特异性动物模型，该模型侧重于溶质-蛋白质相互作用，并表明吲哚溶质以 AHR 和 TF 依赖的方式介导所有 CKD 阶段的高血栓形成表型。我们进一步证明 AHR 通过 STIP1 同源和 U 盒蛋白 1（STUB1）调节 TF。作为一种泛素连接酶，STUB1 通过泛素化在尿毒症环境中动态地与 TF 相互作用并降解 TF。STUB1 对 TF 的调节在人类中得到支持，因为在尿毒症血管中，STUB1 和 TF 的表达呈负相关，并且 STUB1-TF 相互作用减少。血管平滑肌细胞中 STUB1 的遗传或药理学操作抑制了流动回路中的血栓形成。与肝素（CKD 患者标准的抗血栓药物）相比，STUB1 扰动逆转了尿毒症高血栓形成表型，而不会延长出血时间。我们的工作细化了血栓形成轴（STUB1 是吲哚溶质-AHR-TF 轴的介导物），并扩展了对驱动 CKD 中脆弱血栓形成状态的相互关联关系的理解。它还建立了一种在不改变止血平衡的情况下最大限度地减少尿毒症高血栓形成表型的方法，这是 CKD 患者长期以来的追求。
