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

Abstract

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.

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

“…PLAT (plasminogen activator, tissue type) [325] and ALB (albumin) [326] might be involved in the occurrence and development of hypertension. BMI1 [327], AMH (anti-Mullerian hormone) [328], E2F1 [329], PF4 [330], VASH2 [331], GRIN1 [332], CYP11B2 [333], COMP (cartilage oligomeric matrix protein) [334], DES (desmin) [335], ANGPTL3 [336], CYP3A5 [337], DPEP1 [338], LRP2 [339], AGXT2 [340], FABP1 [341], SLC22A12 [342], CUBN (cubilin) [343], MIOX (myo-inositol oxygenase) [344], ARG2 [345], KHK (ketohexokinase) [346], CYP2C8 [347], SLC2A9 [348], GC (GC vitamin D binding protein) [349], VNN1 [350], NOX4 [351], EPHX2 [352], AKR1C3 [353], NR4A3 [354], PFKFB2 [355], SLC22A6 [356], F11 [357], SLC22A2 [358], AQP2 [171], EGF (epidermal growth factor) [359], KNG1 [360], SERPINA5 [361], KL (klotho) [362], ACE2 [363], NPNT (nephronectin) [364], SLC47A1 [358], MGAM (maltase-glucoamylase) [365], AQP3 [366], AZGP1 [367], GALNT3 [368], DPP4 [369], STC1 [370], ABCB1 [371], ERRFI1 [372], TREH (trehalase) [373], MANBA (mannosidase beta) [374], ERBB4 [375], VCAM1 [376] and ALB (albumin) [377] might play an important role in the pathophysiology of AKI. BMI1 [378], IGF2 [379], PRKCB (protein kinase C beta) [380], CCL5 [381], E2F1 [382], PF4 [111], CYP11B2 [383], WNT3A [384], COMP (cartilage oligomeric matrix protein) [385], DES (desmin) [335], ANGPTL3 [386], CYP3A5 [387], LRP2 [388], PAH (phenylalanine hydroxylase) [389], HMGCS2 [390]...…”

“…E2F1 [265], BMI1 [260], VCAM1 [321], AGTR1 [64], hsa-mir-638 [790], hsa-mir-221 [791], FOXC1 [792], YY1 [793], STAT3 [794] and BRCA1 [795] provided a clear picture of the prognosis of patients with hypertension. E2F1 [329], BMI1 [327], VCAM1 [376], USF2 [796], YY1 [797], STAT3 [798] and BRCA1 [799] have always been found in AKI. Identified E2F1 [382], BMI1 [378], VCAM1 [421], AGTR1 [87], MEF2A [800] and STAT3 [798] as a biomarkers for chronic kidney disease.…”

METTL3 mediates SOX5 m6A methylation in bronchial epithelial cells to attenuate Th2 cell differentiation in T2 asthma

“…METTL3, a crucial component of the m6A methyltransferase complex, serves as an active contributor to m6A methylation modifications and participates in immune responses across various diseases, such as breast cancer, infection, and kidney injury [ [23] , [24] , [25] , [26] ]. Within this investigation, a marked decrease in METTL3 expression was observed in the T2 asthma cohort as compared to the normal control group at the clinical, cellular, and animal levels.…”

Pyroptosis: The Determinator of Cell Death and Fate in Acute Kidney Injury

“…IRF2 inhibition reduced the levels of inflammatory factors (IL-1β, IL-18, IL-6, and TNF-α), decreased the expression of Caspase-4 and GSDMD, and improved the survival rate of IRF2−/− mice after CLP. It was suggested that IRF2 deficiency inhibits inflammation and pyroptosis by inhibiting nonclassical inflammasomes [57]. The matrix glycoprotein thrombospondin-1 and upstream stimulatory factor 2 are also highly expressed in SA-AKI patients.…”

“…In vitro MIF knockdown reduced NLRP3 inflammasome-mediated pyroptosis in LPS-damaged HK-2 cells [ 55 ]. Pyroptosis also occurred in renal tubular cells with increased insulin-like growth factor 2 mRNA binding protein 1 [ 56 ].…”