PDF(Pubmed)
Abstract：
Chronic kidney disease (CKD) causes accumulation of uremic metabolites that negatively affect skeletal muscle. Tryptophan-derived uremic metabolites are agonists of the aryl hydrocarbon receptor (AHR), which has been shown to be activated in CKD. This study investigated the role of the AHR in skeletal muscle pathology of CKD. Compared with controls with normal kidney function, AHR-dependent gene expression (CYP1A1 and CYP1B1) was significantly upregulated in skeletal muscle of patients with CKD, and the magnitude of AHR activation was inversely correlated with mitochondrial respiration. In mice with CKD, muscle mitochondrial oxidative phosphorylation (OXPHOS) was markedly impaired and strongly correlated with the serum level of tryptophan-derived uremic metabolites and AHR activation. Muscle-specific deletion of the AHR substantially improved mitochondrial OXPHOS in male mice with the greatest uremic toxicity (CKD + probenecid) and abolished the relationship between uremic metabolites and OXPHOS. The uremic metabolite/AHR/mitochondrial axis in skeletal muscle was verified using muscle-specific AHR knockdown in C57BL/6J mice harboring a high-affinity AHR allele, as well as ectopic viral expression of constitutively active mutant AHR in mice with normal renal function. Notably, OXPHOS changes in AHRmKO mice were present only when mitochondria were fueled by carbohydrates. Further analyses revealed that AHR activation in mice led to significantly increased pyruvate dehydrogenase kinase 4 (Pdk4) expression and phosphorylation of pyruvate dehydrogenase enzyme. These findings establish a uremic metabolite/AHR/Pdk4 axis in skeletal muscle that governs mitochondrial deficits in carbohydrate oxidation during CKD.
摘要：
慢性肾脏疾病（CKD）导致尿毒症代谢产物的积累，对骨骼肌功能产生负面影响。色氨酸衍生的尿毒症代谢物是芳基烃受体（AHR）的激动剂，已显示其在CKD患者的血液中被激活。这项研究调查了AHR在CKD骨骼肌病理中的作用。与肾功能正常的对照组相比，CKD患者骨骼肌中AHR依赖性基因（CYP1A1和CYP1B1）表达明显上调（P=0.032），AHR激活的程度与线粒体呼吸呈负相关（P<0.001）。在患有CKD的小鼠中，肌肉线粒体氧化磷酸化(OXPHOS)显著受损,并与血清色氨酸衍生的尿毒症代谢物水平和AHR激活密切相关.AHR的肌肉特异性缺失显着改善了具有最大尿毒症毒性（CKD丙磺舒）的雄性小鼠的线粒体OXPHOS，并消除了尿毒症代谢物与OXPHOS之间的关系。使用具有高亲和力AHR等位基因的C57BL6J中的肌肉特异性AHR敲除进一步证实了骨骼肌中的尿毒症代谢物-AHR-线粒体轴，以及肾功能正常的小鼠中组成型活性突变体AHR的异位病毒表达。值得注意的是,AHRmKO小鼠的OXPHOS变化仅在线粒体由碳水化合物驱动时才存在。进一步分析显示,小鼠AHR激活导致Pdk4表达(P<0.05)和丙酮酸脱氢酶磷酸化(P<0.05)显著增加。这些发现在骨骼肌中建立了尿毒症代谢物-AHR-Pdk4轴，该轴控制CKD期间碳水化合物氧化中的线粒体缺陷。
