α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5
α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5
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DOI：
10.1152/ajprenal.00143.2012
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发表时间：
2012-11-01
影响因子：
4.2
通讯作者：
Yeh, Ching-Hua
中科院分区：
文献类型：
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作者：
Hsing, Chung-Hsi;Lin, Chiou-Feng;Yeh, Ching-Hua
兴CH，林CF，苏E，孙DP，陈TC，李CF，叶CH。 α(2)-肾上腺素受体激动剂右美托咪定通过增加 BMP-7 和抑制 HDAC2 和 HDAC5 来保护脓毒症急性肾损伤。 Am J Physiol Renal Physiol 303：F1443-F1453，2012。首次发表于 2012 年 8 月 29 日； doi:10.1152/ajprenal.00143.2012.-骨形态发生蛋白 (BMP)-7 可保护脓毒症引起的急性肾损伤 (AKI)。右美托咪定 (DEX) 是一种 α(2)-肾上腺素受体 (α(2)-AR) 激动剂，具有抗炎作用。我们研究了 DEX 对脓毒症诱导的 AKI 以及 BMP-7 和组蛋白脱乙酰酶 (HDAC) 表达的保护作用。在体外，使用实时 PCR 测定 DEX 或曲古抑菌素 A（TSA，一种 HDAC 抑制剂）对 LPS 刺激的大鼠肾小管上皮 NRK52E 细胞中 TNF-α、单核细胞趋化蛋白 (MCP-1)、BMP-7 和 HDAC mRNA 表达的影响。在体内，小鼠在盲肠结扎穿刺（CLP）手术后立即和12小时腹腔注射DEX（25μg/kg）或盐水。 CLP 后 24 小时，我们检查了肾损伤和肾 TNF-α、MCP-1、BMP-7 和 HDAC 表达。监测存活率120小时。 LPS 增加了 NRK52E 细胞中 HDAC2、HDAC5、TNF-α 和 MCP-1 的表达，但降低了 BMP-7 的表达。 DEX 治疗降低了 HDAC2、HDAC5、TNF-α 和 MCP-1 的表达，但增加了 BMP-7 和乙酰组蛋白 H3 的表达，其作用被 α(2)-AR 拮抗剂育亨宾阻断。通过 DEX 处理，scRNAi-NRK52E 细胞中 LPS 诱导的 TNF-α 表达和细胞死亡减弱，但 BMP-7 RNAi-NRK52E 细胞中却没有减弱。在 CLP 小鼠中，DEX 治疗可提高存活率并减轻 AKI。 CLP小鼠肾脏中HDAC2、HDAC5、TNF-α和MCP-1 mRNA表达增加，但BMP-7表达减少。然而，DEX 治疗减少了这些变化。 DEX 通过减少 TNF-α 和 MCP-1 以及增加 BMP-7 来减少脓毒症诱导的 AKI，而 BMP-7 与减少 HDAC2 和 HDAC5 以及增加乙酰组蛋白 H3 相关。
Hsing CH, Lin CF, So E, Sun DP, Chen TC, Li CF, Yeh CH. alpha(2)-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5. Am J Physiol Renal Physiol 303: F1443-F1453, 2012. First published August 29, 2012; doi:10.1152/ajprenal.00143.2012.-Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an alpha(2)-adrenoceptor (alpha(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-alpha, 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 mu g/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-alpha, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-alpha, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-alpha, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an alpha(2)-AR antagonist. With DEX treatment, the LPS-induced TNF-alpha 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-alpha, 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-alpha and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.