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.

Acute kidney injury (AKI) has a high mortality rate, but its pathogenesis remains unclear Lipopolysaccharide (LPS)-mediated renal tubular epithelial pyroptosis is involved in the pathogenesis of AKI. NLR family of pyrin domains containing 3 (NLRP3) plays an important role in pyroptosis. To further understand the transcriptional regulation mechanism of NLRP3, the peripheral blood of patients with AKI was analyzed in this study, showing that the levels of NLRP3 and cell pyroptosis in patients with AKI were significantly higher than those in normal controls. Furthermore, elevated levels of NLRP3 and cell pyroptosis were found in renal tubular epithelial cells after LPS treatment. Transcription factor ETS Proto-Oncogene 1 (ETS1) could bind to the upstream promoter transcription site of NLRP3 to transactivate NLRP3 in renal tubular epithelial cells. The cell pyroptosis level also decreased by knocking down ETS1. It is concluded that knocking down of ETS1 may reduce the renal tubular epithelial pyroptosis by regulating the transcription of NLRP3, thus relieving AKI. ETS1 is expected to be a molecular target for the treatment of AKI. Graphical abstract

Sepsis-associated acute kidney injury (S-AKI) is a critical condition characterized by renal tubular epithelial cell apoptosis and abnormal cytoskeleton. This study aims to investigate the role of the m6A modification-dependent protein HNRNPC in regulating renal cell apoptosis and cytoskeleton in S-AKI. Dot blot analysis was employed to assess the total m6A levels. Cell viability, flow cytometry, and fluorescent phalloidin staining were used to evaluate the role of HNRNPC in CD80-dependent apoptosis and cytoskeletal remodeling. RNA sequencing and subsequent data analysis highlighted the involvement of the NF-κB signaling pathway. Luciferase reporter assays and Western blot were used to establish that HNRNPC transcriptionally promotes CD80 expression. Bioinformatics, EMSA, and ChIP assays further confirmed the role of NF-κB in regulating CD80. Additionally, MeRIP-qPCR and RNA m6A quantification demonstrated that HNRNPC facilitates apoptosis through m6A-dependent regulation of NF-κB. Induction of HNRNPC to a higher level can induce apoptosis and cytoskeletal deformation in renal tubular cells. Meanwhile, CD80 was essential for HNRNPC-induced tubular injury. Further experiments showed that HNRNPC regulated NF-κB mRNA dependent on m6A modification. Moreover, NF-κB acted as a transcription factor to promote CD80 expression. In vivo experiments further verified the relationships between HNRNPC, NF-κB, and CD80 and demonstrated the significance of HNRNPC in CD80-associated apoptosis. This study elucidates the molecular mechanisms underlying the pathogenesis of S-AKI and highlights the potential of HNRNPC and CD80 as therapeutic targets to reduce renal damage in S-AKI. Graphical Abstract

Objective: Idiopathic refractory membranous nephropathy (IRMN) is a subset of nephrotic syndrome with a high risk of progression to end-stage renal disease, yet treatment options remain limited. Obinutuzumab, a humanized type II anti-CD20 antibody, induces efficient CD20+ cell depletion, leading to favorable immunological and proteinuria responses in IRMN. This study sought to assess the effectiveness and safety of obinutuzumab for treating IRMN. Methods: A total of 31 patients with IRMN were enrolled and received obinutuzumab therapy. They were followed for 12 months. The primary endpoint was the remission rate (complete or partial remission). Secondary outcomes included changes in proteinuria, serum albumin, serum creatinine, anti-PLA2R antibody levels, CD20/CD19 cell counts, and adverse events. Results: At 12 months, the overall remission rate was 80%, with 16% achieving complete remission and 64% achieving partial remission. The median time to remission was 4.5 months (IQR 2.0–7.0 months). The immunological remission rates at 3, 6, 9, and 12 months were 70, 83, 90, and 93%, respectively. Regarding anti-PLA2R antibodies, 80% of patients showed a rapid decline within the first 3 months ( p < 0.001), with 64% achieving a > 50% reduction from baseline by month 3. At the last follow-up, all patients had achieved seroconversion to anti-PLA2R antibody negativity. Adverse events included infusion-related reactions such as fever, hypotension, tachycardia, and flushing. No deaths occurred. Conclusion: Obinutuzumab effectively induces remission in patients with IRMN and demonstrates a tolerable safety profile.