Involvement of Klotho, TNF‑α and ADAMs in radiation‑induced senescence of renal epithelial cells

Abstract

While radiation nephropathy is a major problem associated with radiotherapy, the exact mechanisms underlying its pathogenesis and the mediators involved in kidney deterioration remain to be elucidated. In view of the finding that senescence is typically increased post-irradiation, the present study examined whether ionizing radiation may cause kidney injury by enhancing premature senescence. The present study explored the relevance of the aging suppressor, Klotho, which has anti-aging activity and is highly expressed in murine renal cells/kidney tissues, under irradiation conditions. Firstly, the effects of radiation on mouse inner medullary collecting duct-3 (mIMCD-3) cells and kidney tissues of mice were assessed. Subsequently, the mRNA expression levels of Klotho, TNF-α and ADAM metallopeptidase domain (ADAM)9/10/17 were analyzed by reverse transcription-quantitative PCR following exposure to radiation. In addition, the levels of these proteins were measured by western blotting or ELISA. The results revealed that irradiation of mIMCD-3 cells clearly triggered cellular senescence. Notably, Klotho gene expression was considerably decreased in radiation-exposed mIMCD-3 cells and in the kidney tissues of irradiated BALB/c mice, and the corresponding translated protein was consistently expressed following radiation exposure. Moreover, expression of TNF-α, a negative regulator of Klotho, was significantly increased, whereas ADAM9/10/17, an ectodomain shedding enzyme of Klotho, was decreased in irradiated mIMCD-3 cells and in the kidney tissues of BALB/c mice. Collectively, these data suggested that TNF-α-mediated inhibition of Klotho expression and blockage of soluble Klotho formation via decreased ADAM expression following irradiation may contribute to the development of renal dysfunction through acceleration of radiation-induced cellular senescence.

Astaxanthin attenuates irradiation-induced osteoporosis in mice by inhibiting oxidative stress, osteocyte senescence, and SASP

“…53 Klotho mutant mice (C3H) were found to be strongly associated with a remarkable increase in oxidative stress markers. 54 Coincidentally, several studies have shown that the expressions of Nrf2 and klotho were both regulated by radiation exposure, 41,55 suggesting that radiation exposure acting in conjunction with klotho and Nrf2 regulates the expression of many of the antioxidant systems that prevent oxidative stress by removing ROS. Our data indicated that radiation exposure induced an increase in ROS formation, resulting from the reduction of antioxidant gene expression by downregulating Nrf2 and klotho.…”

Cellular senescence: the good, the bad and the unknown

“…Elevated gene expression of the senescence markers T p16 , T p19 and T p53 was also observed in mice with obesity-induced kidney injury 208 and p16 expression was strikingly increased in biopsy samples from patients with glomerular disease 209 . Exposure of kidney cells to nephrotoxic factors including radiation 125 , TNF 210 , hypoxia or glucose oxidase 211 , 212 can induce cell-cycle arrest in vitro. Replicative senescence is also involved in the development of chronic allograft nephropathy 213 .…”

Ageing, cellular senescence and chronic kidney disease: experimental evidence

“…Recent studies have uncovered several novel signal pathways that play a role in exacerbating renal ageing. For example, Wnt/b-catenin is shown to take part in mediating cellular senescence and age-related renal fibrosis [44,45]. Wnt9a/b-catenin activation is associated with renal tubular senescence and renal fibrosis in diseased kidneys, which is accompanied by an increased expression of p16, p53 and p21, and enhanced SA-b-gal activity in renal tubular epithelia [46].…”