title: 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.
authors.affiliation: Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan.
authors.forename: Chung-Hsi
authors.initials: CH
authors.lastname: Hsing
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.forename: Edmund
authors.initials: E
authors.lastname: So
authors.forename: Ding-Ping
authors.initials: DP
authors.lastname: Sun
authors.forename: Tai-Chi
authors.initials: TC
authors.lastname: Chen
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.forename: Ching-Hua
authors.initials: CH
authors.lastname: Yeh
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D002460:Cell Line; D020927:Dexmedetomidine / Q000494:pharmacology / Q000627:therapeutic use*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D055419:Bone Morphogenetic Protein 7; D056572:Histone Deacetylase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D020927:Dexmedetomidine; C498618:Hdac5 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases