earticle

영어

High-dose radiotherapy exposure is associated with normal tissue damage. Moreover, accumulating evidence from the Japanese atomic bomb survivors, Chernobyl liquidators, US astronauts, and some other exposed groups suggest that non-cancer effects also have been observed after moderate/low dose exposure in humans, in particular cardiovascular, respiratory, renal, and brain damage. The late onset of cardiovascular and kidney disease may be highly associated with ionizing radiation, but underappreciated. The exact pathogenesis and/or mediators involved in these chronic disease remain under investigation. Typically, as the senescent cell fraction following irradiation is known to increase, we examined whether ionizing radiation causes the renal injury by inducing cellular senescence. We assessed the effects of ionizing radiation on mouse inner medullary collecting duct- 3 (mIMCD-3) cells and Madin-Darby Canine Kidney (MDCK) cells, which predominantly used in vitro renal epithelial cells. We found that irradiation on mIMCD-3 and MDCK cells induced cellular senescence. Notably, the gene expression level of neuraminidase Klotho, highly expressed in renal cells/tissues with anti-senescence activity, was considerably decreased in irradiated mIMCD-3 cells and also kidney tissues of radiation-exposed mice. However, the protein level of klotho was persistent after radiation exposure. One of the negative regulators of klotho, Tumor necrosis factor-α (TNF-α) was significantly increased in both of irradiated mIMCD-3 cells and kidney tissues of mice. Critically, a Disintegrin and metalloproteinase domain-containing protein 9/10/17 (ADAM9/10/17), which functions as ectodomain shedding enzyme of klotho, was decreased in irradiated mouse renal cells/tissues. Collectively, our data suggest that TNF-α-mediated inhibition of klotho expression with blocking of soluble klotho formation following irradiation may contribute to the development of renal dysfunction through the acceleration of radiation-induced cellular senescence.