Targeting NINJ1-Mediated Plasma Membrane Rupture in Tubular Epithelial Cell Prevents Inflammatory Response in Acute...

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Acute kidney injury (AKI) involves sterile inflammation driven by damage-associated molecular patterns (DAMPs).
• Plasma membrane rupture in renal tubular epithelial cells (RTECs) is a key source of DAMPs during AKI.
• Nerve injury-induced protein 1 (NINJ1) is a newly identified executor of plasma membrane rupture, but its role in AKI is unclear.

Purpose of the Study:

• To investigate the role of NINJ1 in AKI pathophysiology.
• To elucidate the molecular mechanisms regulating NINJ1 in AKI.
• To explore the therapeutic potential of targeting the NINJ1 pathway in AKI.

Main Methods:

• Analysis of NINJ1 expression and oligomerization in human AKI biopsies and mouse models.
• In vitro studies using cultured RTECs subjected to AKI conditions.
• Genetic knockdown of NINJ1 and inhibition of its oligomerization.
• Identification and characterization of transcription factors regulating NINJ1, including ELK1 phosphorylation.
• Pharmacological inhibition of ELK1 activity.

Main Results:

• NINJ1 expression and oligomerization are upregulated in AKI, correlating with plasma membrane rupture, DAMP release, and inflammation.
• NINJ1 knockdown or inhibition of its oligomerization prevents RTEC membrane rupture and reduces inflammation.
• ELK1 is identified as a transcription factor for NINJ1, with phosphorylation at Ser383 enhancing its activity.
• Silencing NINJ1 or inhibiting pELK1 protects against AKI and improves prognosis in mouse models.

Conclusions:

• The ELK1-NINJ1 axis is a critical regulator of plasma membrane rupture in RTECs during AKI.
• Targeting NINJ1 or ELK1 phosphorylation presents a promising therapeutic strategy for AKI.
• This axis offers potential for improving AKI treatment and patient prognosis.