Kidney Week

Abstract: FR-PO816

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

Session Information

• Glomerular Diseases: Inflammation and Immunology
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Gan, Yangang, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China

Yangang Gan

• Yang, Qiongqiong, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China

Qiongqiong Yang, PhD

• Hao, Li, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China

Li Hao, PhD

• Li, Jiajia, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China

Jiajia Li

• Li, Wenchao, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China

Wenchao Li

• Yu, Hao, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China

Hao Yu, MD

• Zeng, Weicong, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China

Weicong Zeng, MD

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.