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Upregulation of Mitochondrial Transcription Factor A Promotes the Repairment of Renal Tubular Epithelial Cells in Sepsis by Inhibiting Reactive Oxygen Species-Mediated Toll-Like Receptor 4/p38MAPK Signaling.

Pathobiology. 2019;86(5-6):263-273. Epub 2019 Aug 20
Xin-Gui Dai 1 , Tao Li 1 , Wei-Bo Huang 2 , Zhen-Hua Zeng 3 , Qiong Li 1 , Yang Yang 1 , Ze-Peng Duan 1 , Yu-Jing Wang 1 , Yu-Hang Ai 4
Xin-Gui Dai 1 , Tao Li 1 , Wei-Bo Huang 2 , Zhen-Hua Zeng 3 , Qiong Li 1 , Yang Yang 1 , Ze-Peng Duan 1 , Yu-Jing Wang 1 , Yu-Hang Ai 4
+ et al

[No authors listed]

Author information
  • 1 Department of Critical Care Medicine, the First People's Hospital of Chenzhou, Chenzhou, China.
  • 2 Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 4 Department of Intensive Care Unit, Xiangya Hospital, Central South University, Changsha, China, ayhicu1978@126.com.

摘要


BACKGROUND:Mitochondrial transcription factor A (TFAM) plays multiple pathophysiologic roles in mitochondrial DNA (mtDNA) maintenance. However, the role of TFAM in sepsis-induced acute kidney injury (AKI) remains largely unknown. METHODS:Lipopolysaccharide (LPS) treatment of HK-2 cells mimics the in vitro model of AKI inflammation. pcDNA3.1 plasmid was used to construct pcDNA3.1-TFAM. sh-TFAM-543, sh-TFAM-717, sh-TFAM-765, sh-TFAM-904 and pcDNA3.1-TFAM were transfected into HK-2 cells using Lipofectamine 2000. MtDNA transcriptional levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR). 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay was performed to assess the cell viability. Changes in reactive oxygen species and mitochondrial membrane potential in HK-2 cells were detected using the corresponding kits. Immunofluorescence experiment was used to investigate the displacement of TFAM. mRNA and protein expression levels of TFAM and its related genes were measured by qRT-PCR and western blot respectively. Mice in sepsis were administered cecal ligation and puncture surgery. RESULTS:LPS treatment was a non-lethal influencing factor, leading to the upregulation of levels and downregulation of mtDNA copy number and NADH dehydrogenase subunit-1 (ND1) expression, and caused damage to the mitochondria. As the LPS treatment time increased, TFAM was displaced from the periphery of the nucleus to cytoplasm. TFAM reduced duanyu1670 and P38MAPK levels by inhibiting toll-like receptor 4 (TLR4) expression, ultimately inhibiting inflammation and repairing mtDNA. CONCLUSIONS:Our results indicate that TFAM repairs mtDNA by blocking the signaling pathway in inflammatory cells, thereby repairing septic tubular epithelial cells, and TFAM may serve as a new target for sepsis therapy.

KEYWORDS: Acute kidney injury, Mitochondrial DNA, Mitochondrial transcription factor A, P38MAPK, Sepsis, Toll-like receptor 4