OncoTargets and Therapy (Feb 2018)

Klotho ameliorates sepsis-induced acute kidney injury but is irrelevant to autophagy

  • Chen X,
  • Tong H,
  • Chen Y,
  • Chen C,
  • Ye J,
  • Mo Q,
  • Zhao G,
  • Hong G,
  • Zheng C,
  • Lu Z

Journal volume & issue
Vol. Volume 11
pp. 867 – 881

Abstract

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Xinxin Chen,1 Huan Tong,2 Yu Chen,3 Chaosheng Chen,1 Jingjing Ye,2 Qingfei Mo,2 Guangju Zhao,2 Guangliang Hong,2 Chenfei Zheng,1 Zhongqiu Lu2 1Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; 2Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; 3Department of Nephrology, Wenzhou Hospital of Traditional Chinese Medicine Affiliated with Zhejiang Chinese Medical University, Wenzhou, Zhejiang, China Background: The role of Klotho (KL) in sepsis-induced acute kidney injury (AKI) and the potential relationship between KL and autophagy in septic AKI were investigated. Materials and methods: A murine model of sepsis-induced AKI was established by cecal ligation and puncture (CLP). Mice undergoing CLP and immortalized proximal tubular epithelial human HK-2 cells that were exposed to lipopolysaccharide (LPS) were treated with recombinant KL, autophagy stimulator rapamycin (Rap), and autophagy suppressor 3-methyladenine (3-MA). Results: Autophagy activation and KL reduction reached maximum levels in mice 24 hours after CLP. Recombinant KL and/or Rap significantly attenuated CLP-induced renal dysfunction (P<0.05) and partially restored endogenous renal KL expression (P<0.05). Recombinant KL had no impact on CLP-induced autophagy and apoptosis, whereas Rap significantly stimulated autophagy and reduced apoptosis in mice. 3-MA significantly exacerbated renal dysfunction, increased apoptosis, and inhibited autophagy in mice with CLP-induced AKI (all P<0.05). In LPS-treated HK-2 cells, Rap significantly enhanced autophagy and reduced apoptosis (all P<0.05), whereas recombinant KL had no impact, and 3-MA inhibited autophagy and significantly increased apoptosis (P<0.05). Conclusion: Recombinant KL alleviates renal dysfunction and restores renal KL expression in mice with sepsis-induced AKI, but the underlying mechanism may not be related to autophagy induction. Keywords: acute kidney injury, autophagy, klotho, septic AKI, Rapamycin, 3-MA

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