Gestational hypertension in atrial natriuretic peptide knockout mice and the developmental origins of salt-sensitivity and cardiac hypertrophy

Regul Pept. 2013 Sep 10:186:108-15. doi: 10.1016/j.regpep.2013.08.006. Epub 2013 Aug 25.

Abstract

Objective: To determine the effect of gestational hypertension on the developmental origins of blood pressure (BP), altered kidney gene expression, salt-sensitivity and cardiac hypertrophy (CH) in adult offspring.

Methods: Female mice lacking atrial natriuretic peptide (ANP-/-) were used as a model of gestational hypertension. Heterozygous ANP+/- offspring was bred from crossing either ANP+/+ females with ANP-/- males yielding ANP+/-(WT) offspring, or from ANP-/- females with ANP+/+ males yielding ANP+/-(KO) offspring. Maternal BP during pregnancy was measured using radiotelemetry. At 14weeks of age, offspring BP, gene and protein expression were measured in the kidney with real-time quantitative PCR, receptor binding assay and ELISA.

Results: ANP+/-(KO) offspring exhibited normal BP at 14weeks of age, but displayed significant CH (P<0.001) as compared to ANP+/-(WT) offspring. ANP+/-(KO) offspring exhibited significantly increased gene expression of natriuretic peptide receptor A (NPR-A) (P<0.001) and radioligand binding studies demonstrated significantly reduced NPR-C binding (P=0.01) in the kidney. Treatment with high salt diet increased BP (P<0.01) and caused LV hypertrophy (P<0.001) and interstitial myocardial fibrosis only in ANP+/-(WT) and not ANP+/-(KO) offspring, suggesting gestational hypertension programs the offspring to show resistance to salt-induced hypertension and LV remodeling. Our data demonstrate that altered maternal environments can determine the salt-sensitive phenotype of offspring.

Keywords: ANP; B-type natriuretic peptide; BNP; BP; CV; CVD; Cardiac hypertrophy; Developmental origins; EIA; HS; Hypertension; IUGR; LV; NPR-A; NPR-C; NPS; NS; Natriuretic peptides; Nppa; Npr1; Npr3; PDE; RIA; Salt-sensitivity; atrial natriuretic peptide; blood pressure; cardiovascular; cardiovascular disease; eNOS; endothelial nitric oxide synthase; enzyme immunoassay; high salt; intrauterine growth restriction; left ventricle; natriuretic peptide precursor A gene; natriuretic peptide receptor 1 gene; natriuretic peptide receptor 3 gene; natriuretic peptide receptor A; natriuretic peptide receptor C; natriuretic peptide system; normal salt; phosphodiesterase; radioimmunoassay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Natriuretic Factor / deficiency
  • Atrial Natriuretic Factor / genetics*
  • Cyclic GMP / metabolism
  • Female
  • Fetal Development
  • Gene Expression
  • Gene Expression Regulation
  • Hypertension, Pregnancy-Induced / genetics*
  • Hypertension, Pregnancy-Induced / metabolism
  • Hypertrophy, Left Ventricular / etiology*
  • Hypertrophy, Left Ventricular / metabolism
  • Kidney / metabolism
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pregnancy
  • Prenatal Exposure Delayed Effects / etiology*
  • Prenatal Exposure Delayed Effects / metabolism
  • Proto-Oncogene Protein c-ets-1 / genetics
  • Proto-Oncogene Protein c-ets-1 / metabolism
  • Receptors, Atrial Natriuretic Factor / genetics
  • Receptors, Atrial Natriuretic Factor / metabolism
  • Salt Tolerance
  • Sodium, Dietary / adverse effects*
  • Ventricular Remodeling
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism

Substances

  • Ets1 protein, mouse
  • Proto-Oncogene Protein c-ets-1
  • Sodium, Dietary
  • Atrial Natriuretic Factor
  • p300-CBP Transcription Factors
  • Receptors, Atrial Natriuretic Factor
  • Cyclic GMP