Long-term exposure of PM2.5 causes hypertension by impaired renal D1 receptor mediated sodium excretion via up-regulation of GRK4 expression in SD rats

BACKGROUND: .Epidemiological evidence supports an important association between air pollution exposure and hypertension. However, the mechanisms are not clear..METHODS AND RESULTS: .Our present study found that long-term exposure to fine particulate matter (PM2.5) causes hypertension and impairs renal sodium excretion, which might be ascribed to lower D1 receptor expression and higher D1 receptor phosphorylation, accompanied with a higher G-protein-coupled receptor kinase type 4 (GRK4) expression. The in vivo results were confirmed in in vitro studies (ie, PM2.5 increased basal and decreased D1 receptor mediated inhibitory effect on Na+-K+ ATPase activity, decreased D1 receptor expression, and increased D1 receptor phosphorylation in renal proximal tubule cells). The downregulation of D1 receptor expression and function might be attributable to a higher GRK4 expression after the exposure of renal proximal tubule cells to PM2.5, because downregulation of GRK4 by small-interfering RNA reversed the D1 receptor expression and function. Because of the role of reactive oxygen species on D1 receptor dysfunction and its relationship with air pollution exposure, we determined plasma reactive oxygen species and found the levels higher in PM2.5-treated Sprague-Dawley rats. Inhibition of reactive oxygen species by tempol (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) reduced blood pressure and increased sodium excretion in PM2.5-treated Sprague-Dawley rats, accompanied by an increase in the low D1 receptor expression, and decreased the hyperphosphorylated D1 receptor and GRK4 expression..CONCLUSIONS: .Our present study indicated that long-term exposure of PM2.5 increases blood pressure by decreasing D1 receptor expression and function; reactive oxygen species, via regulation of GRK4 expression, plays an important role in the pathogenesis of PM2.5-induced hypertension.

背景：流行病学证据支持空气污染暴露与高血压之间存在重要关联。然而，其机制尚不清楚。 方法与结果：我们目前的研究发现，长期暴露于细颗粒物（PM2.5）会导致高血压并损害肾钠排泄，这可能归因于D1受体表达降低和D1受体磷酸化水平升高，同时伴有G蛋白偶联受体激酶4型（GRK4）表达升高。体内结果在体外研究中得到证实（即，PM2.5增加了肾近端小管细胞中基础的以及降低了D1受体介导的对Na⁺ - K⁺ ATP酶活性的抑制作用，降低了D1受体表达，并增加了D1受体磷酸化）。D1受体表达和功能的下调可能是由于肾近端小管细胞暴露于PM2.5后GRK4表达升高，因为小干扰RNA对GRK4的下调逆转了D1受体的表达和功能。由于活性氧对D1受体功能障碍的作用及其与空气污染暴露的关系，我们测定了血浆活性氧，发现PM2.5处理的Sprague - Dawley大鼠中其水平较高。Tempol（4 - 羟基 - 2,2,6,6 - 四甲基哌啶 - 1 - 氧基）对活性氧的抑制降低了PM2.5处理的Sprague - Dawley大鼠的血压并增加了钠排泄，同时伴有低水平的D1受体表达增加，以及高磷酸化的D1受体和GRK4表达降低。 结论：我们目前的研究表明，长期暴露于PM2.5通过降低D1受体的表达和功能来升高血压；活性氧通过调节GRK4的表达，在PM2.5诱导的高血压发病机制中起重要作用。