Abstract: SA-PO578
Irradiation-Induced Glomerular Endothelial Cellular Senescence May Contribute to the Senescence-Associated Secretory Phenotype by Activating the NF-kB Signaling Pathway
Session Information
- Glomerular Diseases: Fibrosis, Extracellular Matrix
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Aratani, Sae, Nippon Medical School Hospital, Tokyo, Japan
- Takahashi, Akiko, Japanese Foundation for Cancer Research, Tokyo, Japan
- Tagawa, Masako, Nippon Medical School, Tokyo, Japan
- Loo, Tze mun, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Sakai, Yukinao, Nippon Medical School Hospital, Tokyo, Japan
- Shimizu, Akira, Nippion Medical School, Tokyo, Japan
- Tsuruoka, Shuichi, Nippon Medical School, Tokyo, Japan
Background
Cellular senescence is one of the major risk factors for chronic kidney disease. We recently reported that ionizing radiation (IR) can cause cellular senescence in the kidney and lead to kidney dysfunction. In this report, we investigated the precise characteristics of radiation-induced cellular senescence in glomerular endothelial cells.
Methods
Male 7-8-week-old rats received unilateral IR of 18 Gy on the kidney (irradiated kidney) or sham IR (normal kidney). We analyzed the presence of cellular senescence and pathological changes until 9 months post IR. In an in vitro experiment, rat glomerular endothelial cells received a single dose of 20 Gy (irradiated cells). Cellular senescence was defined by the combination of senescence-associated β-galactosidase (SA-β-gal), p21, p53, p16 and the senescence-associated secretory phenotype (SASP). The DNA damage response (γH2AX, a marker of DNA double strand breaks) and nuclear factor-kappa B (NF-κB) signaling pathway were also evaluated.
Results
As previously reported, irradiation-induced cellular senescence was demonstrated in the irradiated kidneys. Notably, glomerular endothelial cells in irradiated kidneys displayed more cells that were positively stained for p21 at an earlier time (from 3 months) compared to podocytes. In vitro, irradiation-induced cellular senescence in glomerular endothelial cells was also confirmed. Recent studies reported that the DNA damage response could trigger the NF-kB signaling pathway, resulting in a cascade of inflammation. In our study, irradiated cells showed DNA damage response, and a gradual increase in the expression level of NF-kB mRNA. Irradiated cells also showed nuclear localization of NF-κB and positive staining for phosphorylated IκBα. Once IκBα is phosphorylated, IκB proteins are released from NF-κB. Subsequently, NF-κB translocates to the nucleus and transactivates the expression of target genes. Following the activation of the NF-κB pathway, the various SASP was upregulated at days 20.
Conclusion
Taken together, these data suggest that IR could cause cellular senescence in the kidney. In particular, glomerular endothelial cells may play an important role in production of SASP that might be triggered by the activated NF-kB signaling pathway.