线粒体生物发生
芳香烃受体
纤维化
衰老
化学
下调和上调
肾脏疾病
内分泌学
泛素
泛素连接酶
过氧化物酶体增殖物激活受体
肾
内科学
细胞生物学
线粒体
癌症研究
受体
生物
医学
生物化学
基因
转录因子
作者
Hongyan Xie,Ninghao Yang,Li Lu,Xi-ang Sun,Jingyao Li,Xin Wang,Hengjiang Guo,Li Zhou,Jun Liu,Huijuan Wu,Yu Chen,Wei Zhang,Limin Lü
标识
DOI:10.1002/advs.202402066
摘要
Abstract Retention of metabolic end‐products in the bodily fluids of patients with chronic kidney disease (CKD) may lead to uremia. The uremic toxin indoxyl sulfate (IS), a tryptophan metabolite, is an endogenous ligand of aryl hydrocarbon receptor (AhR). It is clarified that the upregulation and activation of AhR by IS in tubular epithelial cells (TECs) promote renal senescence and fibrosis. Renal TEC‐specific knockout of AhR attenuates renal senescence and fibrosis, as well as the suppression of PGC1α‐mediated mitochondrial biogenesis in ischemia reperfusion (IR)‐ or IS‐treated CKD mice kidneys. Overexpression of peroxisome proliferator‐activated receptor gamma coactivator 1‐α (PGC1α) attenuates IS‐induced cell senescence and extracellular matrix production in cultured TECs. Mechanistically, AhR is able to interact with PGC1α and promotes the ubiquitin degradation of PGC1α via its E3 ubiquitin ligase activity. In summary, the elevation and activation of AhR by the accumulated uremic toxins in the progression of CKD accelerate renal senescence and fibrosis by suppressing mitochondrial biogenesis via promoting ubiquitination and proteasomal degradation of PGC1α.
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