Role of DNA damage in the progress of chronic tubule‑interstitial injury

Sun,Linxiao; Zhu,Xiandong; Luo,Jiao; Wang,Cheng; Chen,Bicheng

doi:10.3892/mmr.2020.11146

Role of DNA damage in the progress of chronic tubule‑interstitial injury

Authors:
- Linxiao Sun
- Xiandong Zhu
- Jiao Luo
- Cheng Wang
- Bicheng Chen
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Affiliations: Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Laboratory Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Published online on: May 14, 2020 https://doi.org/10.3892/mmr.2020.11146
Pages: 1081-1089

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Abstract

Tubulointerstitial fibrosis (TIF) is a common final endpoint of chronic allograft nephropathy. Over the years, several hypotheses have been developed to explain the progression of TIF, including mechanisms such as inflammation, epithelial‑mesenchymal transition, senescence, chronic hypoxia and reactive oxygen species. Furthermore, TIF is reportedly induced by the ‘damage‑proliferation‑death’ cycle. In the present study, an AA renal fibrosis model was established in vitro to investigate whether the vicious proliferation‑death cycle is a pathophysiological process of TIF following chronic injury to the kidneys. Results from the present study revealed that cell death was associated with the entrance of cells into the cell cycle. Genetic knockdown of p21 was observed to increase cell cycle progression and the proliferative rate of cells, which overall promoted increased rates of cell death. In addition, the activation of the DNA damage response (DDR) signaling pathway was demonstrated to be crucial to the initiation of the vicious cycle of ‘proliferation‑death’. Ataxia telangiectasia mutated (ATM) is an important molecule of the DDR and the genetic knockdown of ATM induced apoptosis, increased cell proliferation and promoted cell death. The increase in apoptosis was suggested to be due to the decreased expression levels of p21 observed following the genetic knockdown of ATM. In conclusion, the present study suggested that the crosstalk between the ATM and p21 protein may serve an important role in the regulation of the ‘proliferation‑death’ cycle in the progress of chronic tubulointerstitial injury.

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