Lili Tang, Jie Zhang, Jing Han, Danhong Zhang, Hongtao Zhang, Jun Liu, Xiaoyue Li

Molecular mechanism of circHIPK3 in mitochondrial function in septic acute kidney injury

  • Health, Toxicology and Mutagenesis
  • Management, Monitoring, Policy and Law
  • Toxicology
  • General Medicine
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AbstractCell senescence, glycolysis, and mitochondrial deficit jointly regulate the development of septic acute kidney injury (SAKI). This study aimed to explore the role of circular RNA HIPK3 (circHIPK3) in mitochondrial function in SAKI. The SAKI mouse model was established by Candida albicans infection, followed by Western blot assay, measurements of serum lactate, and adenosine triphosphate (ATP), 5,5′,6,6′‐tetrachloro‐1,1′,3,3′‐tetraethylbenzimi‐dazolylcarbocyanine iodide (JC‐1) staining and flow cytometry. Human renal tubular epithelial cells were treated with lipopolysaccharide to establish the SAKI cell model, followed by cell counting kit‐8 assay, tests of hexokinase activity, lactate production, oxygen consumption rate, extracellular acidification rate, ATP, and JC‐1 staining, and Western blot assay. The roles of mitochondrial pyruvate carrier 1 (MPC1) were validated by kidney function tests, hematoxylin and eosin staining, periodic acid‐Schiff staining, and SA‐β‐gal staining. circHIPK3 downregulation reduced glycolysis and mitochondrial dysfunction both in vivo and in vitro through the microRNA (miR)‐148b‐3p/DNMT1/3a/Klotho axis. Inhibition of miR‐148b‐3p or Klotho increased glycolysis and mitochondrial dysfunction. Knockdown of MPC1 increased lactate content and decreased ATP levels and MMP both in vivo and in vitro. Collectively, circHIPK3, in concert with the miR‐148b‐3p/DNMT1/3a/Klotho axis, increased glycolysis, and inhibited the negative regulation of lactate production by MPC1, and aggravated mitochondrial dysfunction and cell senescence in SAKI.

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