Abstract: TH-PO1177
Histone Deacetylase 4 Facilitates AKI-to-CKD Progression via the Induction of Ferroptosis
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Shen, Fengchen, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Yao, Liyuan, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Du, Xinyu, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Wang, Yanjin, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Yu, Chao, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Yu, Jianjun, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Zhuang, Shougang, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Yan, Zhipeng, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Background
Histone deacetylase 4 (HDAC4) is a member of the HDAC family, and its expression and activation are linked to various diseases, including renal fibrosis. However, its role in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains unclear. This study investigates how HDAC4 regulates this process in a murine model of CKD following severe ischemia/reperfusion injury.
Methods
Renal tubular deficient mice lacking HDAC4 and tasquinimod, a selective PRMT5 inhibitor, were used to reduce HDAC4 expression or suppress its activation in a unilateral ischemia/reperfusion injury (UIRI) model. Histochemical staining was performed to assess pathological changes and fibrosis, while immunostaining evaluated renal expression of HDAC4 and ferroptosis-related proteins. Additionally, immunoblot analysis assessed the expression of proteins associated with renal fibrosis in kidney tissues
Results
Following AKI, NGAL and Kim1 expression levels peaked at 48 hours but decreased by 4 weeks, remaining above baseline. In contrast, collagen I, α-smooth muscle actin (α-SMA), and HDAC4 showed slight increases at 48 hours, with further elevation by 28 days post-IR. HDAC4 was localized in both the cytosol and nuclei of renal tubular cells. Genetic deletion of HDAC4 or tasquinimod administration after I/R significantly improved renal function, reduced pathological changes, and lowered NGAL and Kim1 levels. Mice lacking HDAC4 or treated with tasquinimod seven days post-IR exhibited decreased α-SMA, collagen I, and vimentin expression while maintaining E-cadherin levels. Mechanistic studies indicated that both genetic deletion and pharmacological inhibition reduced ferroptosis as evidenced by lower ACSCL4 (achaete-scute family BHLH transcription factor 4) expression alongside restored glutathione peroxidase 4 and transferrin receptor protein 1 levels. Additionally, HDAC4 deletion or inhibition enhanced Foxo3a acetylation while preserving Sirt3 expression. Finally, a direct interaction between HDAC4 and Foxo3a was observed.
Conclusion
HDAC4 facilitates the progression from AKI to CKD vis a mechanism associated with the induction of ferroptosis.
Funding
- Government Support – Non-U.S.