Knockdown of histone deacetylase 9 ameliorates immunoglobulin a nephropathy by modulating immune response.

Abstract

BACKGROUND: Immunoglobulin A (IgA) nephropathy (IgAN) is a common clinical autoimmune disease, and the regulatory mechanism of Histone deacetylase 9 (HDAC9) in IgAN remains unclear. This study aims to elucidate the therapeutic value and potential mechanisms of HDAC9 in IgA nephropathy, offering potential new targets for clinical intervention and further research. METHODS: An adeno-associated virus 9 (AAV9)-shHDAC9 vector was constructed and investigated the protective effect of HDAC9 knockdown in IgAN mouse. Transcriptome sequencing of renal tissues from IgAN mice was conducted, and immune infiltration analysis was quantified using transcriptomic data analyzed through the CIBERSORT deconvolution algorithm. Flow cytometry was employed to assess the expression of Th17 cell, B cell, and macrophage markers in the kidney tissues of IgAN mice. RESULTS: In vivo animal experiments indicate that HDAC9 knockdown ameliorates renal injury and suppresses the immune system to reduce inflammation in IgAN mice. Transcriptome sequencing results suggest that HDAC9 knockdown may exert therapeutic effects on IgAN by regulating immune-inflammatory responses. Through immune infiltration analysis and single-cell data, we found that HDAC9 may modulate immune cells, particularly T cells, B cells, and macrophages. Flow cytometry further confirmed that HDAC9 knockdown effectively inhibits Th17 cell and B cell activation, as well as macrophage polarization towards the M2 phenotype in IgAN mice. The graphical abstract of this study is shown in Fig. 1. CONCLUSIONS: HDAC9 knockdown modulates immune responses and alleviates pathological damage in IgAN mice. HDAC9 may serve as a potential therapeutic target for IgAN.