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. 2022 Aug 3;18(10):611–627. doi: 10.1038/s41581-022-00601-z

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Fig. 4 — Several stimuli can trigger the senescence of various kidney cell types through different pathways. High glucose levels result in macrophage infiltration into the kidney, mitochondrial dysfunction and activation of NOX1–PKC signalling, which lead to an increase in reactive oxygen species (ROS) and senescence of tubular epithelial cells and endothelial cells. High glucose can also induce senescence of tubular epithelial cells by provoking endoplasmic reticulum (ER) stress, which activates ATF4–p16 signalling. In addition, high glucose induces mesangial cell senescence via AGE–STAT5 signalling, which leads to the inhibition of autophagy and therefore results in the accumulation of injured mitochondrial and ROS (not shown). Nephrotoxic drugs and ageing can induce podocyte and tubular epithelial cell senescence via inhibition of C/EBPα, which leads to a reduction in AMPK–mTOR signalling. Ageing and high glucose can also induce tubular epithelial cell senescence by inhibiting AMPK. Nephrotoxic drugs, ischaemia, radiation and unilateral ureteral obstruction (UUO) activate Wnt–β-catenin signalling, which inhibits autophagy and therefore induces the senescence of tubular epithelial cells. Notably, ischaemia and metabolic syndrome can induce the senescence of kidney scattered tubule-like cells (STCs) and mesenchymal stem cells (MSCs), respectively, resulting in impairment of kidney repair, which promotes progression to chronic kidney disease (CKD). Chronic kidney cell senescence promotes epithelial-to-mesenchymal transition (EMT) and results in the senescence-associated secretory phenotype (SASP), which increases inflammation, eventually leading to the development of fibrosis and CKD. Furthermore, CKD can lead to uraemia-induced senescence of immune cells, endothelial cells, vascular smooth muscle cells and MSCs. CKD is also associated with hyperphosphataemia, which induces senescence in myoblasts, endothelial cells and vascular smooth muscle cells and thereby contributes to sarcopenia and vascular calcification. ADAM, A-disintegrin and metalloproteinase; ATF4, activating transcription factor 4; BRG1, brahma-related gene 1; ILK, integrin-linked protein kinase; NOX1, NADPH oxidase 1; OPTN, optineurin.