INTRODUCTION: Acute kidney injury (AKI) is characterized by a rapid decline in renal function, often associated with tubular cell death. Insulin-induced gene 1 (Insig1), a key regulator of cholesterol metabolism, has not been previously implicated in AKI pathogenesis. OBJECTIVES: This study examines the role of Insig1 in AKI and its underlying mechanisms. METHODS: We combined tubule-specific Insig1 knockout mice subjected to cisplatin or ischemia-reperfusion (I/R) injury with in vitro tubular cell models to define its role in AKI. Proteomics identified Insig1-interacting targets, and pathway inhibition validated the therapeutic potential in cisplatin-AKI mice. RESULTS: We observed significant downregulation of Insig1 in renal biopsies from AKI patients and in mouse models of cisplatin- or I/R-induced AKI. Conditional knockout of Insig1 in renal tubular epithelial cells markedly ameliorated kidney injury in these murine models. Mechanistically, Insig1 was found to interact with death-associated protein kinase 3 (Dapk3), a pro-apoptotic factor, thereby stabilizing Dapk3 protein levels. Knockdown of either Insig1 or Dapk3 in mouse renal tubular epithelial cells (mPTC) attenuated cisplatin-induced cell apoptosis, while their overexpression exacerbated cellular injury. Furthermore, pharmacological Dapk3 inhibition with HS148 recapitulated the renoprotective effects of Insig1 ablation in cisplatin-induced AKI mice. CONCLUSION: Our results unveil a novel Insig1/Dapk3 axis as a critical regulator of AKI progression, highlighting its potential as a therapeutic target in clinic.
Cao et al. (Fri,) studied this question.