R Jensen

Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy

Evidence from human and animal studies suggests that maternal nutrition can induce developmental programming of adult hypertension in offspring. We have previously described a model of maternal dietary imbalance in Sprague‐Dawley rats whereby administration of a maternal diet rich in animal lard programmes the development of increased blood pressure, insulin resistance, dyslipidaemia, obesity and mesenteric artery endothelial dysfunction in adult offspring. To further characterize the mechanism of hypertension in this model we have examined vascular and renal structure in adult offspring of Sprague‐Dawley rats fed a control diet (OC) or lard‐rich diet (OHF) during pregnancy and suckling followed by a control diet post‐weaning. To gain further insight, we assessed aortic reactivity and elasticity in an organ bath preparation and renal renin and Na+,K+‐ATPase activity. Plasma aldosterone concentration was also measured. Stereological examination of the aorta in OHF demonstrated reduced endothelial cell volume and smooth muscle cell number compared with OC. Adult OHF animals showed increased aortic stiffness and reduced endothelium‐dependent relaxation. Renal stereology showed no differences in kidney weight, glomerular number or volume in OHF compared with OC, but renin and Na+,K+‐ATPase activity were significantly reduced in OHF compared with controls. Programmed alterations to aortic structure and function are consistent with previous observations that exposure to maternal high fat diets produces systemic vascular changes in the offspring. Despite normal renal stereology, altered renal Na+,K+‐ATPase and renin activity offers further insight into the mechanism underlying the increased blood pressure characteristic of this model.

Programmed aortic dysfunction and reduced Na+,K+-ATPase activity present in first generation offspring of lard-fed rats does not persist to the second generation

We have previously reported that male and female offspring of Sprague–Dawley rats fed a diet rich (approximately 50% of caloric intake from fat) in animal fat (lard) during pregnancy and suckling (OHF) demonstrate cardiovascular dysfunction, including blunted endothelium‐dependent vasodilatation in the aorta as well as reduced renal Na+,K+‐ATPase activity. Cardiovascular dysfunction has been reported in other models of developmental programming and some researchers describe transmission from F1 to F2 generations. Here we report a study of vascular function, as assessed in isolated rings of aorta mounted in an organ bath, and renal Na+,K+‐ATPase activity in 6‐month‐old male and female F2 offspring of lard‐fed and control‐fed (OC) dams (n= 13 per diet group). An increase in brain (OC 0.61 ± 0.01%versus OHF 0.66 ± 0.02% of bodyweight) and kidney weights (OC 0.32 ± 0.01%versus OHF 0.37 ± 0.01% of bodyweight) was observed in female F2 offspring of lard‐fed dams compared with F2 controls (P < 0.03). Constrictor responses to phenylephrine in the aorta were not different from F2 controls (repeated measures ANOVA, P= 0.85). Also, endothelium‐dependent dilator function, as assessed by responses to acetylcholine (repeated measures ANOVA, P= 0.96) and passive distensibility in the absence of extracellular calcium (repeated measures ANOVA, P= 0.68), was similar. Additionally, renal Na+,K+‐ATPase activity was not statistically different from that observed in control animals (ANOVA, P= 0.89). Although a maternal diet rich in animal fat has deleterious effects on parameters of cardiovascular risk in F1 animals, it does not appear that disorders previously reported in the F1 generation are transmitted to the F2 generation.

Maternal dietary supplementation with saturated, but not monounsaturated or polyunsaturated fatty acids, leads to tissue-specific inhibition of offspring Na+,K+-ATPase

In rats, a maternal diet rich in lard is associated with reduced Na+,K+‐ATPase activity in adult offspring kidney. We have addressed the role of different fatty acids by evaluating Na+,K+‐ATPase activity in offspring of dams fed diets rich in saturated (SFA), monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids. Female Sprague–Dawley rats were fed, during pregnancy and suckling, a control diet (4% w/w corn oil) or a fatty acid supplemented diet (24% w/w). Offspring were reared on chow (4% PUFA) and studied at 6 months. mRNA expression (real‐time PCR) of Na+,K+‐ATPase α subunit and protein expression of Na+,K+‐ATPase subunits (Western blot) were assessed in kidney and brain. Na+,K+‐ATPase activity was reduced in kidney (P < 0.05 versus all groups) and brain (P < 0.05 versus control and MUFA offspring) of the SFA group. Neither Na+,K+‐ATPase α1 subunit mRNA expression, nor protein expression of total α, α1, α2, α3 or β1 subunits were significantly altered in kidney in any dietary group. In brains of SFA offspring α1 mRNA expression (P < 0.05) was reduced compared with MUFA and PUFA offspring, but not controls. Also in brain, SFA offspring demonstrated reduced (P < 0.05) α1 subunit protein and increased phosphorylation (P < 0.05) of the Na+,K+‐ATPase modulating protein phospholemman at serine residue 63 (S63 PLM). Na+,K+‐ATPase activity was similar to controls in heart and liver. In utero and neonatal exposure to a maternal diet rich in saturated fatty acids is associated with altered activity and expression of Na+,K+‐ATPase in adulthood, but mechanisms appear tissue specific.