α₂-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5

Abstract

Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an α(2)-adrenoceptor (α(2)-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro, the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF-α, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 μg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-α, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-α, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-α, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an α(2)-AR antagonist. With DEX treatment, the LPS-induced TNF-α expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-α, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF-α and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

“…In vivo experiments of using the general HDAC inhibitor TSA have shown its role in anti-inflammatory activities through the suppression of cytokines and reactive oxidative species (Blanchard and Chipoy, 2005), and the attenuation of macrophage infiltration (Hsing et al, 2012). By contrast, HDAC inhibitors have shown enhanced synthesis of IL-8 in lung epithelial cells following stimulation with LPS (Iwata et al, 2002) or TNFα (Rahman, 2002).…”

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

“…It also ameliorated sepsis-induced acute kidney injury by decreasing inflammatory cytokine expression, including plasma HMGB1 (15) and increasing the expression of bone morphogenetic protein 7 (14). Pretreatment with DEX also decreased TLR4 expression in tubular cells (15).…”

“…DEX treatment reduced mortality in septic mice (14). It also ameliorated sepsis-induced acute kidney injury by decreasing inflammatory cytokine expression, including plasma HMGB1 (15) and increasing the expression of bone morphogenetic protein 7 (14).…”

“…A study showed that the effect of DEX on reducing inflammation in sepsis may be involved in the epigenetic regulation of cytokine expression (14). The α 2 -AR is a G protein-coupled receptor that transduces signals by catalyzing the dissociation of the G protein and G protein subunits, thus modulating the subunits' downstream effectors.…”

“…G proteins bind to the C terminus of histone deacetylase (HDAC) 5. DEX regulates the HDAC2 and HDAC5 mRNA expression, and the histone H3 acetylation through α 2 -AR (14). Previous reports have shown that DEX-induced cell survival is associated with a decrease in cleaved caspase-3 levels and a reduction of high-mobility group protein B1 (HMGB1) release (15,16).…”