PARylation promotes acute kidney injury via RACK1 dimerization-mediated HIF-1α degradation.
10.1016/j.apsb.2025.07.019
- Author:
Xiangyu LI
1
;
Xiaoyu SHEN
1
;
Xinfei MAO
2
;
Yuqing WANG
1
;
Yuhang DONG
1
;
Shuai SUN
3
;
Mengmeng ZHANG
1
;
Jie WEI
4
;
Jianan WANG
1
;
Chao LI
1
;
Minglu JI
1
;
Xiaowei HU
5
;
Xinyu CHEN
1
;
Juan JIN
6
;
Jiagen WEN
1
;
Yujie LIU
7
;
Mingfei WU
2
;
Jutao YU
1
;
Xiaoming MENG
1
Author Information
1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-Inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230032, China.
2. Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou 310014, China.
3. Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei 230032, China.
4. Department of Nephrology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui, China.
5. Department of Clinical Pharmacy, Anhui Provincial Children's Hospital, Hefei 230051, China.
6. Department of Pharmacology, School of Pharmaceutical Sciences, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, China.
7. Department of Obstetrics and Gynecology, the First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230026, China.
- Publication Type:Journal Article
- Keywords:
Acute kidney injury;
Dimerization;
HIF-1α;
Inflammation;
PARP1;
PARylation;
Phosphorylation;
RACK1
- From:
Acta Pharmaceutica Sinica B
2025;15(9):4673-4691
- CountryChina
- Language:English
-
Abstract:
Poly(ADP-ribosyl)ation (PARylation) is a specific form of post-translational modification (PTM) predominantly triggered by the activation of poly-ADP-ribose polymerase 1 (PARP1). However, the role and mechanism of PARylation in the advancement of acute kidney injury (AKI) remain undetermined. Here, we demonstrated the significant upregulation of PARP1 and its associated PARylation in murine models of AKI, consistent with renal biopsy findings in patients with AKI. This elevation in PARP1 expression might be attributed to trimethylation of histone H3 lysine 4 (H3K4me3). Furthermore, a reduction in PARylation levels mitigated renal dysfunction in the AKI mouse models. Mechanistically, liquid chromatography-mass spectrometry indicated that PARylation mainly occurred in receptor for activated C kinase 1 (RACK1), thereby facilitating its subsequent phosphorylation. Moreover, the phosphorylation of RACK1 enhanced its dimerization and accelerated the ubiquitination-mediated hypoxia inducible factor-1α (HIF-1α) degradation, thereby exacerbating kidney injury. Additionally, we identified a PARP1 proteolysis-targeting chimera (PROTAC), A19, as a PARP1 degrader that demonstrated superior protective effects against renal injury compared with PJ34, a previously identified PARP1 inhibitor. Collectively, both genetic and drug-based inhibition of PARylation mitigated kidney injury, indicating that the PARylated RACK1/HIF-1α axis could be a promising therapeutic target for AKI treatment.
