Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease.
Tryptophan metabolites suppress the Wnt pathway and promote adverse limb events in chronic kidney disease.
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DOI：
10.1172/jci142260
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发表时间：
2022-01-04
期刊：
影响因子：
--
通讯作者：
Chitalia VC
中科院分区：
文献类型：
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作者：
Arinze NV;Yin W;Lotfollahzadeh S;Napoleon MA;Richards S;Walker JA;Belghasem M;Ravid JD;Hassan Kamel M;Whelan SA;Lee N;Siracuse JJ;Anderson S;Farber A;Sherr D;Francis J;Hamburg NM;Rahimi N;Chitalia VC
慢性肾脏病（CKD）对外周动脉疾病（PAD）有很强的独立风险。虽然CKD患者体内保留的溶质（尿毒症溶质）会造成血管损伤，但其在PAD中的作用仍然难以捉摸。在这里，我们表明，饮食中的Dahan衍生的尿毒症溶质，包括硫酸吲哚酚（IS）和犬尿氨酸（Kyn），浓度对应于CKD患者的浓度，抑制几种细胞类型中的β-连环蛋白，包括微血管内皮细胞（EC），抑制Wnt活性和EC中的促血管生成Wnt靶点。机制探测显示，这些尿毒症溶质以依赖于其降解决定子基序中的丝氨酸33和通过芳烃受体（AHR）的方式下调β-连环蛋白。腺嘌呤诱导的CKD和IS溶质特异性小鼠模型的后肢缺血显示毛细血管中β-连环蛋白和VEGF-A减少，毛细血管密度降低，这与EC中IS和Kyn的血液水平和AHR活性呈负相关。AHR抑制剂治疗使CKD小鼠中的缺血后血管生成反应正常化至非CKD水平。在PAD患者的前瞻性队列中，血浆色氨酸代谢物水平和血浆内皮细胞AHR诱导活性显著增加了未来肢体不良事件的风险。这项工作揭示了色氨酸代谢物/AHR/β-连环蛋白轴作为CKD患者微血管稀疏的介质，并证明了其在CKD模型中对PAD的靶向性。
Chronic kidney disease (CKD) imposes a strong and independent risk for peripheral artery disease (PAD). While solutes retained in CKD patients (uremic solutes) inflict vascular damage, their role in PAD remains elusive. Here, we show that the dietary tryptophan-derived uremic solutes including indoxyl sulfate (IS) and kynurenine (Kyn) at concentrations corresponding to those in CKD patients suppress β-catenin in several cell types, including microvascular endothelial cells (ECs), inhibiting Wnt activity and proangiogenic Wnt targets in ECs. Mechanistic probing revealed that these uremic solutes downregulated β-catenin in a manner dependent on serine 33 in its degron motif and through the aryl hydrocarbon receptor (AHR). Hindlimb ischemia in adenine-induced CKD and IS solute–specific mouse models showed diminished β-catenin and VEGF-A in the capillaries and reduced capillary density, which correlated inversely with blood levels of IS and Kyn and AHR activity in ECs. An AHR inhibitor treatment normalized postischemic angiogenic response in CKD mice to a non-CKD level. In a prospective cohort of PAD patients, plasma levels of tryptophan metabolites and plasma’s AHR-inducing activity in ECs significantly increased the risk of future adverse limb events. This work uncovers the tryptophan metabolite/AHR/β-catenin axis as a mediator of microvascular rarefaction in CKD patients and demonstrates its targetability for PAD in CKD models.