Hyperuricemia induces hypertension through activation of renal epithelial sodium channel (ENaC)
Hyperuricemia induces hypertension through activation of renal epithelial sodium channel (ENaC)
复制标题
高尿酸血症通过激活肾上皮钠通道（ENaC）诱发高血压
DOI：
10.1016/j.metabol.2015.10.026
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发表时间：
2016-03-01
影响因子：
9.8
通讯作者：
Liang, Xiubin
中科院分区：
文献类型：
--
作者：
Xu, Weifeng;Huang, Yujie;Liang, Xiubin
目标.高尿酸血症导致高血压的机制尚不清楚。远端肾单位上皮钠通道（ENaC）的活性是钠平衡和血压的重要决定因素。我们的目的是研究高尿酸血症对血压的影响是否与ENaC激活有关。用2%氧嗪酸和6 mg/dl尿酸（UA）诱导大鼠高尿酸血症模型。高尿酸血症大鼠同时给予10 mg/kg/d苯溴马隆（Ben）或1 mg/kg/d阿米洛利（Ami）。使用尾袖监测血压，并采集血液、尿液和肾脏样本。采用Western blotting和免疫组织化学染色法检测肾组织和mCCD细胞中ENaC亚基和ENaC调节复合物（ERC）组分的表达。3周后，高尿酸血症大鼠的血清尿酸（SUA）增加到正常水平的2.5-3.5倍，并保持在这些高水平，直到6周。体内SUA升高后血压升高，肾小管间质损伤，ENaC亚基，SGK 1和GILZ 1的表达增加，Ben治疗可预防这些变化。阿米可明显抑制高尿酸血症大鼠尿钠排泄量的下降。UA诱导所有三个ENaC亚基，SGK 1和GILZ 1的表达，并增加mCCD细胞中的Na+转运。在UA处理的mCCD细胞和高尿酸血症大鼠肾脏中ERK磷酸化水平均显著降低; Ben联合治疗可阻止这种作用。我们的研究结果表明，血清尿酸升高可能通过激活ENaC和调节ERC表达而导致高血压。(C)2015 Elsevier Inc. All rights reserved.
Objectives. The mechanisms leading to hypertension associated with hyperuricemia are still unclear. The activity of the distal nephron epithelial sodium channel (ENaC) is an important determinant of sodium balance and blood pressure. Our aim was to investigate whether the effect of hyperuricemia on blood pressure is related to ENaC activation.Methods. A hyperuricemic model was induced in rats by 2% oxonic acid and 6 mg/dl uric acid (UA). The hyperuricemic rats were co-treated with either 10 mg/kg/d benzbromarone (Ben) or 1 mg/kg/d amiloride (Ami). Blood pressure was monitored using a tail-cuff, and blood, urine, and kidney samples were taken. Western blotting and immunohistochemical staining were performed to determine the expressions of ENaC subunits and components of the ENaC Regulatory Complex (ERC) in kidney tissue or mCCD cells.Results. Serum uric acid (SUA) was increased 2.5-3.5 times above normal in hyperuricemic rats after 3 weeks and remained at these high levels until 6 weeks. The in vivo rise in SUA was followed by elevated blood pressure, renal tubulointerstitial injury, and increased expressions of ENaC subunits, SGK1, and GILZ1, which were prevented by Ben treatment. The decrease in urinary Na+ excretion in hyperuricemic rats was blunted by Ami. UA induced the expression of all three ENaC subunits, SGK1, and GILZ1, and increased Na+ transport in mCCD cells. Phosphorylation of ERK was significantly decreased in both UA-treated mCCD cells and hyperuricemic rat kidney; this effect was prevented by Ben co-treatment.Conclusion. Our findings suggest that elevated serum uric acid could induce hypertension by activation of ENaC and regulation of ERC expression. (C) 2015 Elsevier Inc. All rights reserved.