JCI Insight (Dec 2020)

The negative feedback loop of NF-κB/miR-376b/NFKBIZ in septic acute kidney injury

  • Zhiwen Liu,
  • Chengyuan Tang,
  • Liyu He,
  • Danyi Yang,
  • Juan Cai,
  • Jiefu Zhu,
  • Shaoqun Shu,
  • Yuxue Liu,
  • Lijun Yin,
  • Guochun Chen,
  • Yu Liu,
  • Dongshan Zhang,
  • Zheng Dong

Journal volume & issue
Vol. 5, no. 24

Abstract

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Sepsis is the leading cause of acute kidney injury (AKI). However, the pathogenesis of septic AKI remains largely unclear. Here, we demonstrate a significant decrease of microRNA-376b (miR-376b) in renal tubular cells in mice with septic AKI. Urinary miR-376b in these mice was also dramatically decreased. Patients with sepsis with AKI also had significantly lower urinary miR-376b than patients with sepsis without AKI, supporting its diagnostic value for septic AKI. LPS treatment of renal tubular cells led to the activation of NF-κB, and inhibition of NF-κB prevented a decrease of miR-376b. ChIP assay further verified NF-κB binding to the miR-376b gene promoter upon LPS treatment. Functionally, miR-376b mimics exaggerated tubular cell death, kidney injury, and intrarenal production of inflammatory cytokines, while inhibiting miR-376b afforded protective effects in septic mice. Interestingly, miR-376b suppressed the expression of NF-κB inhibitor ζ (NFKBIZ) in both in vitro and in vivo models of septic AKI. Luciferase microRNA target reporter assay further verified NFKBIZ as a direct target of miR-376b. Collectively, these results illustrate the NF-κB/miR-376b/NFKBIZ negative feedback loop that regulates intrarenal inflammation and tubular damage in septic AKI. Moreover, urinary miR-376b is a potential biomarker for the diagnosis of AKI in patients with sepsis.

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