Inhibition of HDAC enhances STAT acetylation, blocks NF-κB, and suppresses the renal inflammation and fibrosis in Npr1 haplotype male mice

Abstract

Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) plays a critical role in the regulation of blood pressure and fluid volume homeostasis. Mice lacking functional (coding for GC-A/NPRA) exhibit hypertension and congestive heart failure. However, the underlying mechanisms remain largely less clear. The objective of the present study was to determine the physiological efficacy and impact of all--retinoic acid (ATRA) and sodium butyrate (NaBu) in ameliorating the renal fibrosis, inflammation, and hypertension in gene-disrupted haplotype (1-copy; +/-) mice (50% expression levels of NPRA). Both ATRA and NaBu, either alone or in combination, decreased the elevated levels of renal proinflammatory and profibrotic cytokines and lowered blood pressure in mice compared with untreated controls. The treatment with ATRA-NaBu facilitated the dissociation of histone deacetylase (HDAC) 1 and 2 from signal transducer and activator of transcription 1 (STAT1) and enhanced its acetylation in the kidneys of mice. The acetylated STAT1 formed a complex with nuclear factor-κB (NF-κB) p65, thereby inhibiting its DNA-binding activity and downstream proinflammatory and profibrotic signaling cascades. The present results demonstrate that the treatment of the haplotype mice with ATRA-NaBu significantly lowered blood pressure and reduced the renal inflammation and fibrosis involving the interactive roles of HDAC, NF-κB (p65), and STAT1. The current findings will help in developing the molecular therapeutic targets and new treatment strategies for hypertension and renal dysfunction in humans.

Selective inhibition of class IIa histone deacetylases alleviates renal fibrosis

“…HDAC inhibitors have been studied extensively in the treatment of malignancy, and some have gained approval as antitumor therapies (18). Recently, several studies have also demonstrated that HDAC inhibitors are effective in attenuating the development and progression of fibrosis in several organs, including kidney, heart, and lung (19)(20)(21)(22). Most of those observations, however, are based on the use of pan-HDAC inhibitors.…”

Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription

“…The class III HDAC SIRT1 mitigates renal fibrosis, in part, by deacetylating and deactivating SMAD3, a key transcription factor involved in fibrogenesis (Li et al, 2010). HDAC1 and HDAC2 can promote the deacetylation of STAT1, which prevents its binding to and inhibition of NF-κB allowing the latter to stimulate a pro-fibrogenic transcription program in mesangial cells (Kumar et al, 2017). The acetylation status and thus activity of STAT3, a pro-fibrogenic transcription factor, can also be modulated by HDACs during renal fibrosis (Ni et al, 2014).…”

An activity-guided map of electrophile-cysteine interactions in primary human immune cells

“…Despite this mechanistic uncertainty, our studies have uncovered a remarkably selective, electrophile-mediated process for degradation of a key transcriptional regulatory complex in primary human T cells. Considering that HDAC inhibitors have been previously shown to block T cell activation (Takahashi et al, 1996), and HDACs can also support NF-kB function (Jung et al, 2009;Kumar et al, 2017;Wagner et al, 2015), it is possible that the BPK-25-mediated loss of the NuRD complex is relevant to the T cell-suppressive activity of this compound.…”