Peroxisome proliferator-activated receptor-γ agonists repress epithelial sodium channel expression in the kidney
Peroxisome proliferator-activated receptor-γ agonists repress epithelial sodium channel expression in the kidney
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DOI：
10.1152/ajprenal.00306.2011
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发表时间：
2012-03-01
影响因子：
4.2
通讯作者：
Cunard, Robyn
中科院分区：
文献类型：
--
作者：
Borsting, Emily;Cheng, Vicki Pei-Chun;Cunard, Robyn
博尔斯汀E，成VP，玻璃CK，Vallon V，Cunard R.Peroxisome增殖物激活的受体-伽马激动剂抑制肾脏上皮钠通道的表达。AM J Physiol Renal Physiol 302：F540-F551,2012。DOI：10.1152/ajprenal.00306.2011.-Thiazolidinediones(TZDS)，被称为过氧化物酶体增殖物激活受体(PPAR)激动剂，用于治疗2型糖尿病。然而，类似于5%的患者经历了限制治疗的水肿副作用。研究表明上皮钠通道(ENaC)的激活是TZD引起液体滞留的原因之一，尽管有相互矛盾的报道。这项研究的目的是解决PPAR伽马在控制肾脏中ENaC异构体方面的作用。在这里，我们在小鼠身上证明了罗格列酮(RGZ)，一种PPAR伽马配体，可以增加体重和腹部脂肪垫液含量，并降低红细胞压积。RGZ 7d降低肾皮质ENaCα、ENaCβmRNA和ENaCγ蛋白的表达，另一种有效的TZD吡格列酮急性给药5h，不增加肾脏ENaC亚型mRNA和蛋白的表达。吡格列酮还可降低皮质集合管细胞系中ENaCα和ENaC Gamma的mRNA表达。由于还没有进行直接的转录研究，我们研究了PPAR对ENaC的伽马依赖调节。吡格列酮可抑制ENaCγ启动子的活性，这种抑制作用可通过抑制蛋白质合成而部分缓解。染色质免疫沉淀分析表明，抑制与ENaC伽马启动子近端的组蛋白H4K5乙酰化减少有关。综上所述，TZDS不会增加ENaC在肾脏中的表达，事实上是通过间接转录机制抑制ENaC-Gamma启动子。
Borsting E, Cheng VP, Glass CK, Vallon V, Cunard R. Peroxisome proliferator-activated receptor-gamma agonists repress epithelial sodium channel expression in the kidney. Am J Physiol Renal Physiol 302: F540-F551, 2012. First published December 14, 2011; doi: 10.1152/ajprenal.00306.2011.-Thiazolidinediones (TZDs), known as peroxisome proliferator-activated receptor (PPAR) agonists, are used to treat type 2 diabetes. However, similar to 5% of patients experience the treatment-limiting side effect of edema. Studies have implicated activation of the epithelial sodium channel (ENaC) as a cause of TZD-induced fluid retention, although there have been conflicting reports. The goal of this study was to resolve the role of PPAR gamma in control of ENaC isoforms in the kidney. Herein, we demonstrate in mice that rosiglitazone (RGZ), a PPAR gamma ligand, increases body weight and abdominal fat pad fluid content and reduces hematocrit. Seven days of RGZ decreases ENaC alpha and ENaC beta mRNA and ENaC gamma protein expression in the kidney cortex, and acute treatment for 5 h with pioglitazone, another potent TZD, does not increase renal ENaC isoform mRNA or protein expression. Pioglitazone also decreases ENaC alpha and ENaC gamma mRNA expression in a cortical collecting duct cell line. As no direct transcriptional studies had been conducted, we examined the PPAR gamma-dependent regulation of ENaC. Pioglitazone represses ENaC gamma promoter activity, and this repression is partially relieved by inhibition of protein synthesis. Chromatin immunoprecipitation assays revealed that repression is associated with a decrease in histone H4K5 acetylation at the proximal ENaC gamma promoter. In summary, TZDs do not increase ENaC mRNA expression in the kidney, and in fact repress the ENaC gamma promoter via an indirect transcriptional mechanism.