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Published on: November 10, 2021
Insig1 deficiency protects against acute kidney injury via targeting Dapk3
Shihan Cao1, Qian Wang2, Mengyu Zhou1
1Department of Nephrology, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing 210008, Jiangsu, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing 210008, Jiangsu, China; Jiangsu Key Laboratory of Early Development and Chronic Diseases Prevention in Children, Nanjing Medical University, Hanzhong Road #140, Nanjing 210029, Jiangsu, China.
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.
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