KLF4 Promotes Gd-IgA1 Synthesis in B Cells of IgA Nephropathy

Background: B cells are thought to perform a crucial function in IgA nephropathy (IgAN) pathogenesis by generating abnormal IgA1 and antibodies. Nonetheless, the machinery behind the aberrant gene expression of B cells in IgAN patients remains ambiguous. Methods: This study has revealed an extensive range of differences in chromatin accessibility within the B cells of IgAN via ATAC-seq evaluation of active DNA regulatory components. Results: B cells of IgAN were noted to display enhanced chromatin accessibility in genes affiliated with transcription regulation. Moreover, KLF4 was also recognized as a crucial transcription factor supporting the generation of IgA1 and galactose-deficient IgA1 (Gd-IgA1). In vitro, the knockdown of KLF4 suppressed the production of Gd-IgA1 in IgA-secreting cell lines. The study further showed that KLF4 could regulate the expression of genes related to the intestinal immune network for IgA production through RNA-seq. Combining ChIP-seq and RNA-seq, it was found that KLF4 can bind to the IL-6 promoter and regulate its expression. Mechanistically, a luciferase reporter assay verified that KLF4 directly binds to the cis-regulatory element of IL-6 and promotes its expression. KLF4 knockdown has been demonstrated to mitigate renal lesions and mesangial hypercellularity in IgAN mice. Conclusion: Findings from this study reveal a mechanism mediated by chromatin underlying the differential responses of B cells in IgAN and identify KLF4 as a potential therapeutic target of IgAN. Funding: Government Support – Non-U.S.