ADENOSINE MONOPHOSPHATE-ACTIVATED PROTEIN KINASE PHOSPHORYLATION MEDIATED BY SIRTUIN 5 ALLEVIATES SEPTIC ACUTE KIDNEY INJURY

Shock. 2023 Mar 1;59(3):477-485. doi: 10.1097/SHK.0000000000002073. Epub 2022 Dec 19.

Abstract

Background : Our previous studies have shown that ameliorating mitochondrial damage in renal tubular epithelial cells (RTECs) can alleviate septic acute kidney injury (SAKI). It is reported that AMPK phosphorylation (p-AMPK) could ameliorate mitochondrial damage in renal tissue and Sirtuin 5 (SIRT5) overexpression significantly enhanced the level of p-AMPK in bovine preadipocytes. However, the role of SIRT5-mediated phosphorylation of AMPK in SAKI needs to be clarified. Methods : WT/SIRT5 gene knockout mouse model of cecal ligation and puncture-induced SAKI and a human kidney 2 cell model of LPS-induced SAKI were constructed. An AMPK chemical activator and SIRT5 overexpression plasmid were used. Indexes of mitochondrial structure and function, level of p-AMPK, and expression of SIRT5 protein in renal tissue and RTECs were measured. Results : After sepsis stimulation, the p-AMPK level was decreased, mitochondrial structure was disrupted, and ATP content was decreased. Notably, an AMPK activator alleviated SAKI. Sirtuin 5 gene knockout significantly aggravated SAKI, while SIRT5 overexpression alleviated mitochondrial dysfunction after LPS stimulation, as manifested by the increase of p-AMPK level, the alleviation of mitochondrial structure damage, the restoration of ATP content, the decrease of proapoptotic protein expression, as well as the reduction of reactive oxygen species generation. Conclusions : Upregulation of SIRT5 expression can attenuate mitochondrial dysfunction in RTECs and alleviate SAKI by enhancing the phosphorylation of AMPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Acute Kidney Injury*
  • Adenosine Monophosphate
  • Adenosine Triphosphate / metabolism
  • Animals
  • Cattle
  • Humans
  • Lipopolysaccharides / metabolism
  • Mice
  • Phosphorylation
  • Sepsis* / metabolism
  • Sirtuins*

Substances

  • AMP-Activated Protein Kinases
  • Adenosine Monophosphate
  • Lipopolysaccharides
  • Sirtuins
  • Adenosine Triphosphate