Long‐Term Exposure of Fine Particulate Matter Causes Hypertension by Impaired Renal D1 Receptor–Mediated Sodium Excretion via Upregulation of G‐Protein–Coupled Receptor Kinase Type 4 Expression in Sprague‐Dawley 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 (PM 2.5 ) causes hypertension and impairs renal sodium excretion, which might be ascribed to lower D 1 receptor expression and higher D 1 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, PM 2.5 increased basal and decreased D 1 receptor mediated inhibitory effect on Na + ‐K + ATPase activity, decreased D 1 receptor expression, and increased D 1 receptor phosphorylation in renal proximal tubule cells). The downregulation of D 1 receptor expression and function might be attributable to a higher GRK4 expression after the exposure of renal proximal tubule cells to PM 2.5 , because downregulation of GRK4 by small‐interfering RNA reversed the D 1 receptor expression and function. Because of the role of reactive oxygen species on D 1 receptor dysfunction and its relationship with air pollution exposure, we determined plasma reactive oxygen species and found the levels higher in PM 2.5 ‐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 PM 2.5 ‐treated Sprague‐Dawley rats, accompanied by an increase in the low D 1 receptor expression, and decreased the hyperphosphorylated D 1 receptor and GRK4 expression. Conclusions Our present study indicated that long‐term exposure of PM 2.5 increases blood pressure by decreasing D 1 receptor expression and function; reactive oxygen species, via regulation of GRK4 expression, plays an important role in the pathogenesis of PM 2.5 ‐induced hypertension.