Role of renal DJ-1 in the pathogenesis of hypertension associated with increased reactive oxygen species production.
Role of renal DJ-1 in the pathogenesis of hypertension associated with increased reactive oxygen species production.
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DOI：
10.1161/hypertensionaha.111.185744
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Jose PA
中科院分区：
文献类型：
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作者：
Cuevas S;Zhang Y;Yang Y;Escano C;Asico L;Jones JE;Armando I;Jose PA
D2多巴胺受体（D2R）在原发性高血压的发病机制中起重要作用。我们已经报道了小鼠D2R基因的系统性缺失导致活性氧（ROS）依赖性高血压，这表明D2R具有抗氧化作用。然而，这种作用的机制尚不清楚。DJ-1是一种具有抗氧化特性的蛋白质。D2R和DJ-1在小鼠肾脏中表达，并在小鼠肾近端小管细胞中共定位和共免疫沉淀。我们假设D2Rs通过调节DJ-1的表达或功能来调节肾脏中ROS的产生。杂合子D2+/−小鼠血压、尿8-异前列腺素和肾Nox 4表达升高，但肾DJ-1表达降低。沉默小鼠肾近端小管细胞中D2R的表达可增加ROS的产生，降低DJ-1的表达。相反，用D2R激动剂处理这些细胞会增加DJ-1表达，降低Nox 4表达和NADPH氧化酶活性，这些作用被D2R拮抗剂部分阻断。在小鼠肾近端小管细胞中沉默DJ-1表达可增加ROS生成和Nox 4表达。通过囊下滴注DJ-1 siRNA选择性沉默小鼠肾脏DJ-1，可提高血压、肾脏Nox 4表达和NADPH氧化酶活性。这些结果表明，D2R对肾脏ROS生成的抑制作用至少在一定程度上是由DJ-1表达/功能的正向调节介导的，DJ-1可能在预防与ROS生成增加相关的高血压中起作用。
The D2 dopamine receptor (D2R) is important in the pathogenesis of essential hypertension. We have already reported that systemic deletion of the D2R gene in mice results in reactive oxygen species (ROS)-dependent hypertension, suggesting that the D2R has antioxidant effect. However, the mechanism of this effect is unknown. DJ-1 is a protein which has antioxidant properties. D2R and DJ-1 are expressed in the mouse kidney and colocalize and co-imunoprecipitate in mouse renal proximal tubule cells. We hypothesized that D2Rs regulate renal ROS production in the kidney through regulation of DJ-1 expression or function. Heterozygous D2+/− mice have increased blood pressure, urinary 8-isoprostanes, and renal Nox 4 expression, but decreased renal DJ-1 expression. Silencing D2R expression in mouse renal proximal tubule cells increases ROS production and decreases the expression of DJ-1. Conversely, treatment of these cells with a D2R agonist increases DJ-1 expression and decreases Nox 4 expression and NADPH oxidase activity, effects that are partially blocked by a D2R antagonist. Silencing DJ-1 expression in mouse renal proximal tubule cells increases ROS production and Nox 4 expression. Selective renal DJ-1 silencing by the subcapsular infusion of DJ-1 siRNA in mice increases blood pressure, and renal Nox 4 expression and NADPH oxidase activity. These results suggest that the inhibitory effects of D2R on renal ROS production are at least, in part, mediated by a positive regulation of DJ-1 expression/function and that DJ-1 may have a role in the prevention of hypertension associated with increased ROS production.