Background/Aims: Adverse environment in utero can modulate adult phenotypes including blood pressure. Fine particulate matter (PM_2.5) exposure in utero causes hypertension in the offspring, but the exact mechanisms are not clear. Renal dopamine D₁ receptor (D₁R), regulated by G protein-coupled receptor kinase type 4 (GRK4), plays an important role in the regulation of renal sodium transport and blood pressure. In this present study, we determined if renal D₁R dysfunction is involved in PM_2.5–induced hypertension in the offspring. Methods: Pregnant Sprague–Dawley rats were given an oropharyngeal drip of PM_2.5 (1.0 mg/kg) at gestation day 8, 10, and 12. The blood pressure, 24-hour sodium excretion, and urine volume were measured in the offspring. The expression levels of GRK4 and D₁R were determined by immunoblotting. The phosphorylation of D₁R was investigated using immunoprecipitation. Plasma malondialdehyde and superoxide dismutase levels were also measured in the offspring. Results: As compared with saline-treated dams, offspring of PM_2.5-treated dams had increased blood pressure, impaired sodium excretion, and reduced D₁R-mediated natriuresis and diuresis, accompanied by decreased renal D₁R expression and GRK4 expression. The impaired renal D₁R function and increased GRK4 expression could be caused by increased reactive oxidative stress (ROS) induced by PM_2.5 exposure. Administration of tempol, a redox-cycling nitroxide, for 4 weeks in the offspring of PM_2.5-treated dam normalized the decreased renal D₁R expression and increased renal D₁R phosphorylation and GRK4 expression. Furthermore, tempol normalized the increased renal expression of c-Myc, a transcription factor that regulates GRK4 expression. Conclusions: In utero exposure to PM_2.5 increases ROS and GRK4 expression, impairs D₁R-mediated sodium excretion, and increases blood pressure in the offspring. These studies suggest that normalization of D₁R function may be a target for the prevention and treatment of the hypertension in offspring of mothers exposed to PM_2.5 during pregnancy.

BackgroundEpidemiological evidence supports an important association between air pollution exposure and hypertension. However, the mechanisms are not clear.Methods and ResultsOur 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, PM 2.5 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 PM 2.5, 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 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 D1 receptor expression, and decreased the hyperphosphorylated D1 receptor and GRK4 expression.ConclusionsOur present study indicated that long‐term exposure of PM 2.5 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 PM 2.5‐induced hypertension.