Inhibition of IGF2BP1 attenuates renal injury and inflammation by alleviating m6A modifications and E2F1/MIF pathway.

Autor:	Mao Y; Department of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China., Jiang F; Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China., Xu XJ; Department of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China., Zhou LB; Department of Dermatology, Suzhou Hospital, Nanjing Medical University, Suzhou, China., Jin R; Department of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China., Zhuang LL; Department of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China., Juan CX; Department of Nephrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China., Zhou GP; Department of Pediatrics, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Jazyk:	angličtina
Zdroj:	International journal of biological sciences [Int J Biol Sci] 2023 Jan 01; Vol. 19 (2), pp. 593-609. Date of Electronic Publication: 2023 Jan 01 (Print Publication: 2023).
DOI:	10.7150/ijbs.78348
Abstrakt:	Septic acute kidney injury (AKI) is characterized by inflammation. Pyroptosis often occurs during AKI and is associated with the development of septic AKI. This study found that induction of insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to a higher level can induce pyroptosis in renal tubular cells. Meanwhile, macrophage migration inhibitory factor (MIF), a subunit of NLRP3 inflammasomes, was essential for IGF2BP1-induced pyroptosis. A putative m6A recognition site was identified at the 3'-UTR region of E2F transcription factor 1 (E2F1) mRNA via bioinformatics analyses and validated using mutation and luciferase experiments. Further actinomycin D (Act D) chase experiments showed that IGF2BP1 stabilized E2F1 mRNA dependent on m6A. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) indicated that E2F1 acted as a transcription factor to promote MIF expression. Thus, IGF2BP1 upregulated MIF through directly upregulating E2F1 expression via m6A modification. Experiments on mice with cecum ligation puncture (CLP) surgery verified the relationships between IGF2BP1, E2F1, and MIF and demonstrated the significance of IGF2BP1 in MIF-associated pyroptosis in vivo . In conclusion, IGF2BP1 was a potent pyroptosis inducer in septic AKI through targeting the MIF component of NLRP3 inflammasomes. Inhibiting IGF2BP1 could be an alternate pyroptosis-based treatment for septic AKI. Competing Interests: Competing Interests: The authors have declared that no competing interest exists. (© The author(s).)
Databáze:	MEDLINE
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