Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk

Area of Science:

• Nephrology
• Vascular Biology
• Biochemistry

Background:

• Chronic kidney disease (CKD) increases atherothrombosis risk and bleeding complications.
• Mechanisms linking uremic solutes, vascular proteins (tissue factor [TF], aryl hydrocarbon receptor [AHR]), and thrombosis/bleeding risks are unclear.
• Indolic uremic solutes are implicated in CKD-related vascular dysfunction.

Purpose of the Study:

• To elucidate the mechanisms by which indolic solutes drive hyperthrombosis in CKD.
• To investigate the role of the aryl hydrocarbon receptor (AHR) and tissue factor (TF) in this process.
• To identify potential therapeutic targets for managing thrombotic risks in CKD without affecting hemostasis.

Main Methods:

• Development of an indolic solute-specific animal model for CKD.
• Investigation of AHR- and TF-dependent pathways.
• Analysis of STIP1 homology and U-box-containing protein 1 (STUB1) as a ubiquitin ligase regulating TF.
• Inhibition of STUB1 in vascular smooth muscle cells and assessment of thrombosis and bleeding in flow loops.
• Human studies correlating STUB1 and TF expression in uremic vessels.

Main Results:

• Indolic solutes mediate a hyperthrombotic phenotype in CKD via an AHR- and TF-dependent mechanism.
• AHR regulates TF through STUB1, a ubiquitin ligase that degrades TF via ubiquitination in the uremic environment.
• Human uremic vessels show an inverse relationship between STUB1 and TF expression and reduced STUB1-TF interaction.
• STUB1 manipulation in vascular smooth muscle cells inhibited thrombosis without prolonging bleeding time.
• STUB1 perturbations reversed the uremic hyperthrombotic phenotype, unlike heparin.

Conclusions:

• STUB1 acts as a key mediator in the indolic solute-AHR-TF axis, refining the understanding of CKD thrombosis.
• Targeting STUB1 offers a novel strategy to mitigate hyperthrombosis in CKD without compromising hemostatic balance.
• This approach presents a promising therapeutic avenue for CKD patients facing both thrombotic and bleeding risks.