Abstract: FR-PO162
Trap1 Lactylation Promotes Tubular Regeneration after AKI through Modulation of PIF1 Transcription
Session Information
- AKI: Mechanisms
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Li, Jinhua, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Zhuang, Hongjie, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Yang, Jiayi, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Zeng, Shuhan, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Bai, Xiaoyan, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Ye, Zhiming, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
- Yu, Xueqing, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
Background
Recent studies have identified that the modification of histone protein lysine (K) residues by lactylation (La) promotes a wound healing gene transcription profile in macrophages, suggesting that lysine lactylation (KLa) may have a broader role in regulating the tissue repair response. Aim of the study is to identify which KLa has potential to enhance regeneration after acute kidney injury (AKI) and investigate the mechanism by which the identified KLa drives the repair process.
Methods
AKI model was established by a peritoneal injection of folic acid (FA). Mass spectrometry was performed to identify the KLa as a potential regeneration driver after AKI from 5-day FA nephropathy. The biological function of the identified KLa was corroborated with wild type and mutant mice in which lysine was replaced with T to mimic persistent KLa or replaced with R to mimic blockade of lactylation of lysine. Renal function was assessed by histology and biochemical parameters.
Results
Four KLa sites were identified through mass spectrometryand bioinformatic analysis. They were individually overexpressed in the mouse renal tubular epithelial cells (MTEC) via a retroviral vector. The cell proliferation assay clearly demonstrated that Trap1 K126T significantly enhanced MTEC proliferation with the proliferative capability K126T > WT > K126R under both normoxia and hypoxia conditions. Confocal microscopy demonstrated that the number of Pax8+/Ki67+/K126La+ cells were significantly higher than that of Pax8+/Ki67-/K126La+ in human chronic kidney disease (CKD) and FA nephropathy. There were no differences in serum creatinine levels at day 2 after FA administration; but at days 5 and 7 the serum creatinine levels declined faster in Trap1 K126T mice and reduced fibrosis on day 28 compared with WT and Trap1 K126R mice. RNA seq and IP/WB identified that Trap1 K126T upregulates transcription of PIF1 through interaction with Nat14, while PIF1, a DNA-dependent ATPase and 5'-3' DNA helicase can efficiently unwind G-quadruplex (G4) DNA structures and forked RNA-DNA hybrids and resolve G4 structures, preventing replication pausing and double-strand breaks (DSBs) at G4 motifs.
Conclusion
Trap1 K126La promotes tubular regeneration after AKI through modulation of PIF1 expression. Trap1 K126La may be a therapeutic target in AKI-CKD transition.
Funding
- Government Support – Non-U.S.