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

Abstract

ObjectiveTo 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. MethodsFemale 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. ResultsANP+/−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.