Down-regulating HDAC2-LTA4H pathway ameliorates renal ischemia-reperfusion injury

The activation of histone deacetylase 2 (HDAC2) is the main pathogenesis of acute kidney injury (AKI), one of the leading causes of end-stage kidney disease. However, the regulatory role of HDAC2 upregulation on inflammation in AKI is still unclear.

In this study, we found that treatment with HDAC2 inhibitor BRD6688 could mitigate the degree of mesangial sclerosis, interstitial infiltration and tubular atrophy, reduce the concentration of blood urea nitrogen (BUN) and serum creatinine (Scr), improve the proliferation, anti-apoptotic, anti-oxidative stress and angiogenesis effects of renal cells. Our results mainly indicated that renal HDAC2 activity was increased by casein kinase 2 (CK2) in renal ischemia reperfusion (I/R) models, and HDAC2 genetic ablation in HREpiC cells suppressed the leukotriene B4 (LTB4) production. Renal leukotriene A4 hydrolase (LTA4H) activity was increased in AKI mice in a HDAC2-dependent manner. LTB4 could induce monocytes to differentiate into M1 macrophages, while BRD6688 could suppress this effect and force the M1 macrophages polarize to M2 macrophages.

Inhibition of HDAC2 activities by BRD6688 could suppress the progression of renal I/R injury through the regulation of LTA4H and macrophage polarization.