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

Ping Zhou, Dongdong Li, Fuli Luo, Xiaoxiao Wan

Gene 2022 Jul 20

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Dysregulation of multiple genes is an important risk factor for acute kidney injury (AKI). Numerous genes, such as proinflammatory cytokines, intracellular cell adhesion molecules (ICAMs), and nitric oxide synthases (NOSs), are implicated in AKI pathogenesis. However, the molecular mechanisms involved in the dysregulation of these genes are still obscure. Herein, we discovered that two subunits of NF-κB (p50 and p65) couple with lysine acetyltransferase 2B (KAT2B) and nuclear receptor coactivator 2 (NOCA2) to assemble a transcriptional complex in a LPS-induced mouse model of AKI. The NCOA2-KAT2B-NF-κB complex bound to the promoters of some NF-κB target genes, such as interleukin 1 beta (IL-1B), IL-6, tumor necrosis factor alpha (TNFA), ICAM1, vascular cell adhesion molecule 1 (VCAM1), cluster of differentiation 38 (CD38), CD40, CD80, and NOS2, and transactivated their expression. In vitro knockdown of components of the NCOA2-KAT2B-NF-κB complex or blockage of KAT2B by its inhibitors (5-chloro-2-(4-nitrophenyl)-3(2H)-isothiazolone [CNIT] and garcinol) significantly decreased the expression of these NF-κB target genes following LPS treatment. The administration of CNIT and garcinol significantly improved the in vivo outcomes of the AKI mice. Our findings reveal the underlying mechanism of NF-κB target upregulation in the pathogenesis of LPS-induced AKI and identify a new therapeutic strategy for AKI that involves targeting the NCOA2-KAT2B-NF-κB complex. Copyright © 2022 Elsevier B.V. All rights reserved.

Citation

Ping Zhou, Dongdong Li, Fuli Luo, Xiaoxiao Wan. NCOA2 coordinates with the transcriptional KAT2B-NF-κB partner to trigger inflammation response in acute kidney injury. Gene. 2022 Jul 20;832:146583