In Utero Exposure to Fine Particulate Matter Causes Hypertension Due to Impaired Renal Dopamine D1 Receptor in Offspring

Cell Physiol Biochem. 2018;46(1):148-159. doi: 10.1159/000488418. Epub 2018 Mar 21.

Abstract

Background/aims: Adverse environment in utero can modulate adult phenotypes including blood pressure. Fine particulate matter (PM2.5) 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 PM2.5-induced hypertension in the offspring.

Methods: Pregnant Sprague-Dawley rats were given an oropharyngeal drip of PM2.5 (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 PM2.5-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 PM2.5 exposure. Administration of tempol, a redox-cycling nitroxide, for 4 weeks in the offspring of PM2.5-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 PM2.5 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 PM2.5 during pregnancy.

Keywords: Dopamine D1 receptor; Fetal origins of adult disease; Fine particulate matter; Hypertension; Oxidative stress.

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Cyclic N-Oxides / pharmacology
  • Diuresis / drug effects
  • Down-Regulation / drug effects*
  • Female
  • Fenoldopam / pharmacology
  • Gestational Age
  • Hypertension / etiology*
  • Hypertension / metabolism
  • Kidney / metabolism*
  • Oxidative Stress / drug effects
  • Particulate Matter / toxicity*
  • Phosphorylation / drug effects
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / metabolism*
  • Spin Labels
  • Superoxide Dismutase / metabolism
  • Up-Regulation / drug effects

Substances

  • Cyclic N-Oxides
  • Particulate Matter
  • Receptors, Dopamine D1
  • Spin Labels
  • Superoxide Dismutase
  • Fenoldopam
  • tempol