Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease

Area of Science:

• Vascular Biology
• Nephrology
• Metabolic Disease

Background:

• Chronic kidney disease (CKD) is a significant risk factor for peripheral artery disease (PAD).
• Uremic solutes accumulating in CKD contribute to vascular damage, but their specific role in PAD pathogenesis is unclear.
• Tryptophan-derived uremic solutes are implicated in vascular dysfunction.

Purpose of the Study:

• To investigate the role of dietary tryptophan-derived uremic solutes in mediating microvascular rarefaction and PAD development in CKD.
• To elucidate the molecular mechanisms linking uremic solutes, β-catenin signaling, and angiogenesis in the context of CKD and PAD.
• To assess the therapeutic potential of targeting the identified pathway in CKD-associated PAD.

Main Methods:

• In vitro studies using microvascular endothelial cells (ECs) exposed to indoxyl sulfate (IS) and kynurenine (Kyn).
• In vivo studies using adenine-induced CKD and IS solute-specific mouse models with hindlimb ischemia.
• Assessment of β-catenin, VEGF-A, capillary density, and aryl hydrocarbon receptor (AHR) activity.
• Pharmacological inhibition of AHR in CKD mouse models.
• Prospective cohort study of PAD patients measuring plasma tryptophan metabolites and AHR activity.

Main Results:

• IS and Kyn suppressed β-catenin and Wnt activity in ECs by interacting with the aryl hydrocarbon receptor (AHR).
• CKD and IS models exhibited reduced capillary density and diminished proangiogenic factors, correlating with elevated IS/Kyn levels and AHR activity.
• AHR inhibition restored the angiogenic response in CKD mice.
• In PAD patients, higher plasma tryptophan metabolites and AHR-inducing activity predicted increased risk of adverse limb events.

Conclusions:

• The tryptophan metabolite/AHR/β-catenin axis is a key mediator of microvascular rarefaction in CKD patients.
• This pathway contributes to the increased risk of PAD in individuals with CKD.
• Targeting the AHR pathway offers a potential therapeutic strategy for PAD in CKD.