Abstract: SA-PO0176
Trap1 Lactylation Enhances Tubular Regeneration After AKI via C1orf21 and DNA Repair Activation
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Li, Jinhua, Department of Nephrology, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
- Zhuang, Hongjie, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Yang, Jiayi, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Zeng, Shuhan, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Su, Jianan, Department of Nephrology, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
- Chen, Yubing, Department of Nephrology, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
- Wang, Qing, Department of Nephrology, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
- Bai, Xiaoyan, Department of Nephrology, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
- Ye, Zhiming, Department of Nephrology, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
- Yu, Xueqing, Department of Nephrology, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
Background
Despite advances in the detection of acute kidney injury (AKI), there are currently no specific therapies to promote recovery or prevent progression to chronic kidney disease (CKD). Recent studies have shown that histone lysine lactylation (KLa) can drive a wound-healing gene expression profile in macrophages, suggesting a broader role for KLa in tissue repair. This study aims to identify specific KLa that enhances tubular regeneration following AKI and to elucidate the underlying mechanism by which KLa promotes renal repair.
Methods
KLa proteomics in a mouse model of the AKI-CKD transition, along with cell culture, were used to screen and identify which KLa has the potential to promote tubular regeneration. The biological function of the identified KLa was validated in three mouse models of AKI-CKD transition. Mechanistic study included CUT&Tag, EMSA, molecular simulations, and screening of a lead compound library.
Results
Trap1 K128 lactylation was identified as a potential driver of tubular regeneration following AKI. In human CKD renal biopsies, proliferating tubular cells expressing Trap1 KLa showed a positive correlation with eGFR. The functional role of Trap1 KLa was validated in mouse models of folic acid-induced nephropathy, bilateral ischemia-reperfusion injury, and unilateral ureteral obstruction. A Trap1 K128T mutant, which mimics sustained KLa, promoted renal regeneration. Conversely, the K128R mutant, mimicking blockade of KLa, impaired renal recovery. Notably, Trap1 KLa was found to accumulate in the nucleus during the AKI-CKD transition.
Trap1 KLa binds the promoter region of C1orf21 (Cf21), as demonstrated by CUT&Tag and EMSA. Overexpression of Cf21 enhanced, while its knockout reduced, proliferation of renal tubular epithelial cells (HK2) following hypoxia-reoxygenation (H/R) injury. Cf21 enhanced DNA repair gene transcription as demonstrated by CUT&Tag, EMSA and RT-qPCR in HK2 cells. Molecular simulations and library screening based on Trap1 structure identified a candidate compound that increased Trap1 KLa levels, Cf21 promoter activity, and HK2 cell proliferation under H/R injury.
Conclusion
Trap1 KLa facilitates renal regeneration after AKI by regulating Cf21 and DNA repair gene transcription and may represent a novel therapeutic target in the AKI-CKD transition.
Funding
- Government Support – Non-U.S.