TY - JOUR
T1 - The negative feedback loop of NF-κB/ miR-376b/NFKBIZ in septic acute kidney injury
AU - Liu, Zhiwen
AU - Tang, Chengyuan
AU - He, Liyu
AU - Yang, Danyi
AU - Cai, Juan
AU - Zhu, Jiefu
AU - Shu, Shaoqun
AU - Liu, Yuxue
AU - Yin, Lijun
AU - Chen, Guochun
AU - Liu, Yu
AU - Zhang, Dongshan
AU - Dong, Zheng
N1 - Funding Information:
This study was supported in part by National Natural Science Foundation of China (81720108008, 81870475).
Publisher Copyright:
Copyright: © 2020, Liu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2020/12/17
Y1 - 2020/12/17
N2 - 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.
AB - 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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U2 - 10.1172/jci.insight.142272
DO - 10.1172/jci.insight.142272
M3 - Article
C2 - 33328388
AN - SCOPUS:85097841915
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 24
M1 - e142272
ER -