1. Uremic Toxin Receptor AhR Facilitates Renal Senescence and Fibrosis via Suppressing Mitochondrial Biogenesis
- Author
-
Hongyan Xie, Ninghao Yang, Li Lu, Xi'ang Sun, Jingyao Li, Xin Wang, Hengjiang Guo, Li Zhou, Jun Liu, Huijuan Wu, Chen Yu, Wei Zhang, and Limin Lu
- Subjects
aryl hydrocarbon receptor ,cell senescence ,mitochondrial biogenesis ,PGC1α ,renal fibrosis ,Science - Abstract
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.
- Published
- 2024
- Full Text
- View/download PDF