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

Damage-associated molecular patterns (DAMPs)-induced sterile inflammation is considered as a typical feature of acute kidney injury (AKI). Plasma membrane rupture in renal tubular epithelial cells (RTECs) is the major cause of DAMP release and nerve injury-induced protein 1 (NINJ1) has recently emerged as an executor of plasma membrane rupture, while its role in AKI pathophysiology remains largely unknown. Here, we show upregulated NINJ1 expression and oligomerization in renal tubules among human biopsies and mouse models as well as in cultured RTECs after AKI, accompanied by plasma membrane rupture, increased DAMP release and inflammatory response. Furthermore, knockdown of NINJ1 or inhibition of its oligomerization effectively prevents plasma membrane rupture in RTECs, thereby alleviating DAMP-induced inflammatory response and renal tubular injury. Mechanistically, the ETS transcription factor (ELK1) is identified as a novel transcription factor for NINJ1 during AKI, especially ELK1 phosphorylation at Ser³⁸³ significantly enhances its transcriptional activity. Importantly, genetic silencing of NINJ1 or pharmacological inhibition of Ser³⁸³-phosphorylated ELK1 can protect against AKI and improve AKI prognosis. Collectively, these findings highlight the ELK1-NINJ1 axis as a pivotal regulator of plasma membrane rupture in RTECs upon AKI, suggesting that it may serve as a potential target for AKI treatment and prognosis improvement.

acute kidney injury.; damage-associated molecular pattern; inflammation; nerve injury-induced protein 1 (NINJ1); plasma membrane rupture.