Role of Thioredoxin 1 in Impaired Renal Sodium Excretion of hD 5 R (F173L) Transgenic Mice.
Role of Thioredoxin 1 in Impaired Renal Sodium Excretion of hD 5 R (F173L) Transgenic Mice.
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硫氧还蛋白 1 在 hD 5 R (F173L) 转基因小鼠肾钠排泄受损中的作用。
DOI：
10.1161/jaha.119.012192
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发表时间：
2019
影响因子：
5.4
通讯作者：
Zeng Chunyu
中科院分区：
文献类型：
--
作者：
Wang Shaoxiong;Tan Xiaorong;Chen Peng;Zheng Shuo;Ren Hongmei;Cai Jin;Zhou Lin;Jose Pedro A;Yang Jian;Zeng Chunyu
多巴胺D5受体（D5 R）通过调节肾脏钠转运而在维持血压中起重要作用。我们先前的研究发现，人D5 R突变F173 L转基因（hD 5 RF 173 L-TG）小鼠具有高血压。方法和结果与野生型D5 R-TG（hD 5 RWT-TG）小鼠相比，hD 5 RF 173 L-TG小鼠血压升高，基础尿流量和钠排泄减少，激动剂介导的尿钠排泄和利尿功能受损。hD 5 RF 173 L-TG小鼠中活性氧产生的增强部分是由抗氧化酶（包括硫氧还蛋白1（Trx 1））的表达减少引起的。Na+-K+-ATP酶活性在hD 5 RF 173 L转染的小鼠肾近端小管细胞中增加，但通过外源性重组人Trx 1蛋白处理恢复正常。D5 R通过磷脂酶C/蛋白激酶C（PKC）途径调节Trx 1，因为在磷脂酶C或PKC抑制剂存在下，D1 R敲除小鼠的肾近端小管细胞中不会发生D5 R上调Trx 1表达。非诺多泮是一种D1 R和D5 R激动剂，可刺激hD 5 RWT-TG小鼠原代肾近曲小管细胞中的PKC活性，但在hD 5 RF 173 L-TG小鼠中则不然。hD 5 RF 173的过度磷酸化及其与Gαs和Gαq的解离与D5 R介导的Na+-K+-ATP酶活性的抑制作用在hD 5 RF 173 L-TG mice. Conclusions这些表明thathD 5 RF 173 L升高血压，部分是通过降低肾脏Trx 1表达和增加活性氧产生。hD 5 RF 173 L的过度磷酸化及其与Gαs和Gαq的解离是hD 5 RF 173 L-TG小鼠D5 R功能受损的关键因素。
BackgroundDopamine D5receptor (D5R) plays an important role in the maintenance of blood pressure by regulating renal sodium transport. Our previous study found that human D5R mutant F173L transgenic (hD5RF173L‐TG) mice are hypertensive. In the present study, we aimed to investigate the mechanisms causing this renal D5R dysfunction inhD5RF173L‐TG mice.Methods and ResultsCompared with wild‐type D5R‐TG (hD5RWT‐TG) mice,hD5RF173L‐TG mice have higher blood pressure, lower basal urine flow and sodium excretion, and impaired agonist‐mediated natriuresis and diuresis. Enhanced reactive oxygen species production inhD5RF173L‐TG mice is caused, in part, by decreased expression of antioxidant enzymes, including thioredoxin 1 (Trx1). Na+‐K+‐ATPase activity is increased in mouse renal proximal tubule cells transfected withhD5RF173L, but is normalized by treatment with exogenous recombinant human Trx1 protein. Regulation of Trx1 by D5R occurs by the phospholipase C/ protein kinase C (PKC) pathway because upregulation of Trx1 expression by D5R does not occur in renal proximal tubule cells from D1R knockout mice in the presence of a phospholipase C or PKC inhibitor. Fenoldopam, a D1R and D5R agonist, stimulates PKC activity in primary renal proximal tubule cells ofhD5RWT‐TG mice, but not in those ofhD5RF173L‐TG mice. Hyperphosphorylation of hD5RF173Land its dissociation from Gαs and Gαq are associated with impairment of D5R‐mediated inhibition of Na+‐K+‐ATPase activity inhD5RF173L‐TG mice.ConclusionsThese suggest thathD5RF173Lincreases blood pressure, in part, by decreasing renal Trx1 expression and increasing reactive oxygen species production. Hyperphosphorylation of hD5RF173L, with its dissociation from Gαs and Gαq, is the key factor in impaired D5R function ofhD5RF173L‐TG mice.