Abstract
Currently, cellular senescence has emerged as a fundamental contributor to chronic organ diseases. Radiation is one of the stress factors that induce cellular senescence. Although the kidney is known as a radiosensitive organ, whether and how radiation-induced cellular senescence is associated with kidney diseases remains unclear. In this study, we performed experiments on 7–8-week-old male rats that received a single dose of 18-Gy radiation in the unilateral kidney. The irradiated kidneys showed hallmarks of cellular senescence, including increased SA-β-gal activity, upregulation of cyclin-dependent kinase inhibitor (p53, p21, and p16), and absence of DNA proliferation marker (Ki-67). Furthermore, combined with in-vitro experiments, we demonstrated that radiation-induced senescent glomerular endothelial cells acquired altered gene expression, namely, senescence-associated secretory phenotype (particularly, IL-6), which might be triggered by NF-kB signaling pathway. Pathological analysis suggested severe glomerular endothelial cell injury, as evidenced by thrombotic microangiopathy, collapsing glomeruli, and reduced endothelial cell numbers. We suggested that glomerular endothelial cells were more susceptible to radiation-induced cellular senescence. In conclusion, the current study is the first to identify the important role of radiation-induced cellular senescence, mainly derived from glomerular endothelial cells, for the development of glomerular injury.
Highlights
Cellular senescence has emerged as a fundamental contributor to chronic organ diseases[1,2,3], such as cardiovascular diseases[4,5], lung fibrosis[6,7], neurovascular diseases[8,9], skin injury[10], hematopoietic stem cell dysfunction[11], and chronic kidney diseases (CKD)[3,12]
We aimed to examine the role of radiation-induced cellular senescence in the development of kidney diseases, glomerular injury
We demonstrated radiation-induced cellular senescence in the glomerular endothelial cells and podocytes
Summary
Cellular senescence has emerged as a fundamental contributor to chronic organ diseases[1,2,3], such as cardiovascular diseases[4,5], lung fibrosis[6,7], neurovascular diseases[8,9], skin injury[10], hematopoietic stem cell dysfunction[11], and chronic kidney diseases (CKD)[3,12]. First documented by Domagk in 192720, spans over a long term after exposure to radiation, and is characterized by proteinuria, azotemia, hypertension, and anemia[21,22]. It causes cellular damages in all components of the kidney, including the glomerulus, blood vessels, tubular epithelium, and interstitials[23]. Recent studies have shown that radiation-induced cellular senescence contributes to the progress of organ diseases. We aimed to examine the role of radiation-induced cellular senescence in the development of kidney diseases, glomerular injury. Renal failure, and glomerular changes were analyzed over the following nine months
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