Work

The Positive Feedback Regulation of NF-κB/miR-21c/IL-9 Axis in Septic Acute Kidney Injury

Year: 2026

Type: article

Abstract: KEY POINTS: Our study identifies a pathogenic NF-κB/microRNA-21c/IL-9 feedback loop that amplifies renal inflammation and injury in sepsis-associated AKI. MicroRNA-21c was significantly upregulated in renal proximal tubules during LPS-induced sepsis-associated AKI. BACKGROUND: Sepsis-associated AKI (septic AKI) is a leading cause of mortality in critically ill patients. Despite its high prevalence, no specific therapies are currently available, primarily because the molecular mechanisms that sustain renal inflammation and tubular damage remain poorly understood. METHODS: A murine model of LPS-induced septic AKI and cultured murine proximal tubular (Boston University mouse proximal tubular) cells were used. In vivo , anti-microRNA-21c (miR-21c) or miR-21c mimic was administered through tail vein injection before LPS challenge. Molecular interactions were assessed by chromatin immunoprecipitation, luciferase reporter assay, quantitative PCR, Western blotting, immunohistochemistry, and fluorescence in situ hybridization. Renal function and injury were evaluated by serum creatinine, BUN, histopathology, and terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining. RESULTS: miR-21c was significantly upregulated in renal proximal tubules during LPS-induced septic AKI, coinciding with peak renal dysfunction and tubular damage. This upregulation was driven by NF-κB because LPS induced p65 nuclear translocation, and pharmacologic inhibition of NF-κB blocked miR-21c induction. Chromatin immunoprecipitation assays confirmed direct binding of p65 to the miR-21c promoter. Subsequent dual-luciferase reporter assays specifically validated the binding site as the functional response element. Functional studies showed that inhibition of miR-21c attenuated kidney injury, reducing serum creatinine and BUN levels, alleviating histological damage, decreasing tubular apoptosis, and suppressing proinflammatory cytokines. Conversely, overexpression of miR-21c exacerbated all injury parameters. Mechanistically, miR-21c directly targeted the 3'-untranslated region of IL-9, as validated by luciferase reporter assay, resulting in reduced IL-9 protein expression. Restoration of IL-9 in tubular cells suppressed LPS-induced apoptosis and inflammation. Importantly, IL-9 overexpression specifically inhibited phosphorylation of NF-κB p65. CONCLUSIONS: Our study identified a pathogenic NF-κB/miR-21c/IL-9 feedback loop that amplified renal inflammation and injury in septic AKI. Targeting miR-21c or enhancing IL-9 signaling may offer novel therapeutic strategies to mitigate kidney damage and improve outcomes in septic patients.

Source: Kidney360

DOI: 10.34067/kid.0000001240

Authors: Zheng Li, Juan Wang, Lei Zhang, Zhiwen Liu

Institutions: Central South University, Second Xiangya Hospital of Central South University

Language: English

Topic: Acute Kidney Injury Research

Subfield: Nephrology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: diamond

Funders: National Natural Science Foundation of China, Central South University, Xiangya Hospital, Central South University