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

• Published in: American journal of physiology. Renal physiology 2012-11, Vol.303 (10), p.F1443-F1453
• Main Authors: Hsing, Chung-Hsi, Lin, Chiou-Feng, So, Edmund, Sun, Ding-Ping, Chen, Tai-Chi, Li, Chien-Feng, Yeh, Ching-Hua
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Acute Kidney Injury - prevention & control; Adrenergic alpha-2 Receptor Agonists - pharmacology; Adrenergic alpha-2 Receptor Agonists - therapeutic use; Animals; Bone Morphogenetic Protein 7 - metabolism; Cell Line; Dexmedetomidine - pharmacology; Dexmedetomidine - therapeutic use; Histone Deacetylase 2 - antagonists & inhibitors; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - metabolism; Kidney - drug effects; Kidney - metabolism; Mice; Rats; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1522-1466
• DOI: 10.1152/ajprenal.00143.2012

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.