Integrated Stress Response and Drug-Induced Acute Kidney Injury: Involvement of Activating ATF4-STAT1-GBP2 Signaling.

Abstract

Integrated stress response promotes drug-induced AKI. Activating transcription factor 4 promoted tubular epithelial cell pyroptosis in drug-induced AKI by activating signal transducer and activator of transcription 1-guanylate-binding protein 2 signaling. Pyroptosis plays a critical role in eliminating pathogens and facilitating tissue repair; however, sustained pyroptosis-driven inflammation accelerates kidney injury and disease progression. Thus, elucidating the mechanisms governing pyroptosis is essential for developing effective therapies for inflammatory kidney diseases, such as AKI, which currently lacks specific treatment options. Changes in tubular epithelial cells (TEC) after drug-induced AKI were assessed using single-cell RNA sequencing, immunohistochemistry, and immunofluorescence. Mechanistic insights were obtained through RNA sequencing, genomic manipulation, transcriptomic profiling, luciferase reporter assays, coimmunoprecipitation, and Western blotting. TEC fate was further evaluated using transgenic mouse models and pharmacological interventions. We identified activating transcription factor 4 (ATF4) as a key regulator of inflammation in drug-induced AKI. As the master regulator of the integrated stress response, ATF4 was markedly upregulated in renal tubules and positively correlated with kidney dysfunction in both human and murine AKI models. The specific deletion of ATF4 in TECs significantly ameliorated kidney dysfunction, inflammation, and mitochondrial apoptosis, whereas ATF4 activation exacerbated these pathological features. Mechanistically, ATF4 suppression inhibited signal transducer and activator of transcription 1 phosphorylation and disrupted its interaction with guanylate-binding protein 2, thereby attenuating NLR family pyrin domain-containing 3 inflammasome activation, preventing TECs' pyroptosis, and improving kidney function. Notably, inhibition of ATF4-either pharmacologically using our prioritized integrated stress response antagonist ERMT1 or through engineered nanobiologics-mediated silencing of TECs-significantly reduced renal inflammation and injury. ATF4 promoted pyroptosis in drug-induced AKI through signal transducer and activator of transcription 1-guanylate-binding protein 2 signaling.