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

Area of Science:

• Nephrology
• Molecular Biology
• Immunology

Background:

• Sepsis is a primary cause of acute kidney injury (AKI), but its underlying mechanisms are not fully understood.
• MicroRNAs (miRNAs) play critical roles in cellular processes and disease pathogenesis.

Purpose of the Study:

• To investigate the role of microRNA-376b (miR-376b) in the pathogenesis of septic AKI.
• To evaluate the diagnostic potential of urinary miR-376b in patients with sepsis-associated AKI.

Main Methods:

• Assessed miR-376b levels in renal tubular cells and urine of mice with septic AKI.
• Analyzed urinary miR-376b in human sepsis patients with and without AKI.
• Investigated the regulatory pathway involving NF-κB, miR-376b, and NFKBIZ using cell culture and animal models.
• Utilized Chromatin Immunoprecipitation (ChIP) and luciferase reporter assays.

Main Results:

• miR-376b levels were significantly decreased in renal tubular cells and urine during septic AKI in mice.
• Lower urinary miR-376b levels were observed in sepsis patients with AKI compared to those without AKI.
• NF-κB activation by LPS reduced miR-376b expression, and NF-κB directly bound to the miR-376b promoter.
• miR-376b exacerbated tubular injury and inflammation, while its inhibition was protective.
• miR-376b directly targeted and suppressed NF-κB inhibitor ζ (NFKBIZ).

Conclusions:

• A novel NF-κB/miR-376b/NFKBIZ negative feedback loop regulates kidney inflammation and tubular damage in septic AKI.
• Urinary miR-376b serves as a potential diagnostic biomarker for AKI in sepsis patients.