NCOA2 coordinates with the transcriptional KAT2B-NF-κB partner to trigger inflammation response in acute kidney...

Area of Science:

• Molecular Biology
• Immunology
• Nephrology

Background:

• Acute kidney injury (AKI) involves complex gene dysregulation.
• Key genes in AKI pathogenesis include proinflammatory cytokines, ICAMs, and NOSs.
• The precise molecular mechanisms driving this gene dysregulation remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms behind NF-κB target gene dysregulation in LPS-induced AKI.
• To identify a novel transcriptional complex involved in AKI pathogenesis.
• To explore potential therapeutic targets for AKI.

Main Methods:

• Utilized a lipopolysaccharide (LPS)-induced mouse model of AKI.
• Investigated the interaction of NF-κB subunits (p50, p65) with KAT2B and NCOA2.
• Assessed the binding of the NCOA2-KAT2B-NF-κB complex to target gene promoters.
• Performed in vitro knockdown experiments and utilized KAT2B inhibitors (CNIT, garcinol).
• Evaluated the therapeutic efficacy of inhibitors in vivo.

Main Results:

• Identified a transcriptional complex composed of NCOA2, KAT2B, and NF-κB (p50/p65).
• This complex directly binds to and activates promoters of key AKI-associated genes (IL-1B, IL-6, TNFA, ICAM1, VCAM1, CD38, CD40, CD80, NOS2).
• In vitro knockdown and inhibition of KAT2B significantly reduced target gene expression post-LPS.
• Administration of CNIT and garcinol ameliorated AKI in vivo.

Conclusions:

• The NCOA2-KAT2B-NF-κB complex is a critical mediator of NF-κB target gene upregulation in LPS-induced AKI.
• Targeting this complex presents a promising therapeutic strategy for AKI.
• KAT2B inhibitors demonstrate potential for treating AKI.