In Utero Exposure to Fine Particulate Matter Causes Hypertension Due to Impaired Renal Dopamine D 1 Receptor in Offspring

Abstract

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 D 1 receptor (D 1 R), 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 D 1 R 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 D 1 R were determined by immunoblotting. The phosphorylation of D 1 R 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 D 1 R-mediated natriuresis and diuresis, accompanied by decreased renal D 1 R expression and GRK4 expression. The impaired renal D 1 R 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 D 1 R expression and increased renal D 1 R 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 D 1 R-mediated sodium excretion, and increases blood pressure in the offspring. These studies suggest that normalization of D 1 R function may be a target for the prevention and treatment of the hypertension in offspring of mothers exposed to PM 2.5 during pregnancy.