Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure
Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure
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DOI：
10.1172/jci.insight.85888
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发表时间：
2016-06-02
期刊：
影响因子：
8
通讯作者：
Armando, Ines
中科院分区：
文献类型：
--
作者：
Konkalmatt, Prasad R.;Asico, Laureano D.;Armando, Ines
多巴胺D2受体（DRD 2）缺乏会增加小鼠的肾脏炎症和血压。我们在这里表明，使用siRNA长期肾脏选择性沉默Drd 2增加了小鼠肾脏促炎和促纤维化因子的表达和血压。为了确定肾选择性拯救小鼠中DRD 2表达的效果，首先使用siRNA沉默DRD 2的肾表达，14天后通过逆行肾输注具有DRD 2的腺相关病毒（AAV）载体来拯救。肾DRD 2 siRNA治疗使DRD 2蛋白的肾表达降低55%，而DRD 2 AAV治疗使DRD 2蛋白的肾表达增加7.5至10倍。肾选择性DRD 2补救减少了促炎因子的表达和肾损伤，保留了肾功能，并使收缩压和舒张压正常化。这些结果表明，肾选择性DRD 2沉默对肾功能和血压的有害影响通过肾选择性过表达DRD 2来挽救。此外，45分钟双侧缺血/再灌注对小鼠肾功能和血压的有害影响通过在诱导缺血/再灌注损伤后立即通过逆行输尿管输注DRD 2 AAV来选择性增加DRD 2表达而得到改善。因此，缺血/再灌注损伤后14天，输注DRD 2 AAV的小鼠的促纤维化因子、血清肌酐和血压的肾表达低于输注对照AAV的小鼠。这些结果表明肾DRD 2在限制肾损伤和维持正常肾功能和血压中的重要作用。
Dopamine D2 receptor (DRD2) deficiency increases renal inflammation and blood pressure in mice. We show here that long-term renal-selective silencing of Drd2 using siRNA increases renal expression of proinflammatory and profibrotic factors and blood pressure in mice. To determine the effects of renal-selective rescue of Drd2 expression in mice, the renal expression of DRD2 was first silenced using siRNA and 14 days later rescued by retrograde renal infusion of adeno-associated virus (AAV) vector with DRD2. Renal Drd2 siRNA treatment decreased the renal expression of DRD2 protein by 55%, and DRD2 AAV treatment increased the renal expression of DRD2 protein by 7.5- to 10-fold. Renal-selective DRD2 rescue reduced the expression of proinflammatory factors and kidney injury, preserved renal function, and normalized systolic and diastolic blood pressure. These results demonstrate that the deleterious effects of renal-selective Drd2 silencing on renal function and blood pressure were rescued by renal-selective overexpression of DRD2. Moreover, the deleterious effects of 45-minute bilateral ischemia/reperfusion on renal function and blood pressure in mice were ameliorated by a renal-selective increase in DRD2 expression by the retrograde ureteral infusion of DRD2 AAV immediately after the induction of ischemia/reperfusion injury. Thus, 14 days after ischemia/reperfusion injury, the renal expression of profibrotic factors, serum creatinine, and blood pressure were lower in mice infused with DRD2 AAV than in those infused with control AAV. These results indicate an important role of renal DRD2 in limiting renal injury and preserving normal renal function and blood pressure.