Abstract
Hypertension is common and contributes, via cardiovascular disease, towards a large proportion of adult deaths in the Western World. High salt intake leads to high blood pressure, even when occurring prior to birth – a mechanism purported to reside in altered kidney development and later function. Using a combination of in vitro and in vivo approaches we tested whether increased maternal salt intake influences fetal kidney development to render the adult individual more susceptible to salt retention and hypertension. We found that salt-loaded pregnant rat dams were hypernatraemic at day 20 gestation (147±5 vs. 128±5 mmoles/L). Increased extracellular salt impeded murine kidney development in vitro, but had little effect in vivo. Kidneys of the adult offspring had few structural or functional abnormalities, but male and female offspring were hypernatraemic (166±4 vs. 149±2 mmoles/L), with a marked increase in plasma corticosterone (e.g. male offspring; 11.9 [9.3–14.8] vs. 2.8 [2.0–8.3] nmol/L median [IQR]). Furthermore, adult male, but not female, offspring had higher mean arterial blood pressure (effect size, +16 [9–21] mm Hg; mean [95% C.I.]. With no clear indication that the kidneys of salt-exposed offspring retained more sodium per se, we conducted a preliminary investigation of their gastrointestinal electrolyte handling and found increased expression of proximal colon solute carrier family 9 (sodium/hydrogen exchanger), member 3 (SLC9A3) together with altered faecal characteristics and electrolyte handling, relative to control offspring. On the basis of these data we suggest that excess salt exposure, via maternal diet, at a vulnerable period of brain and gut development in the rat neonate lays the foundation for sustained increases in blood pressure later in life. Hence, our evidence further supports the argument that excess dietary salt should be avoided per se, particularly in the range of foods consumed by physiologically immature young.
Highlights
Between a quarter and a third of the world’s adult population suffer from hypertension and as a result are significantly predisposed towards diseases of the cardiovascular system (CVD) including stroke, coronary and/or ischemic heart disease [1]
Dietary salt-loading leads to maternal hypernatraemia In rats fed excess dietary salt for 4 weeks prior to conception and to day 4 gestation, plasma osmolality was significantly increased (29662 vs. 27862 mosmoles/kg H2O for salt diet (SD) vs. control diet (CD) dams, respectively)
Continued dietary salt-loading maintained this difference in maternal plasma osmolality, for example, when measured at day 20 gestation (Table 1) or at weaning (31564 vs. 29665 mosmoles/kg H2O for SD vs. CD dams, respectively)
Summary
Between a quarter and a third of the world’s adult population suffer from hypertension and as a result are significantly predisposed towards diseases of the cardiovascular system (CVD) including stroke, coronary and/or ischemic heart disease [1]. Guyton first proposed the ‘pressure-natriuresis’ hypothesis as the main long-term mechanism for control of blood pressure [15] One implication of this hypothesis was that a latent inability of the kidneys to effectively excrete salt over a wide range of intake (perhaps due to a ‘programmed’ deficit in function) drives an increase in arterial pressure, resulting in a higher pressor set-point (or ‘hypertension’) over which salt-balance is achieved. Maternal malnutrition may impact upon both of these aspects of kidney function in the offspring, a programmed deficit in nephron number has received most attention (for review see [18]) Whilst such a phenotype may in the long-term contribute toward, or associate with, a tendency for increased blood pressure [19] the inherent physiological redundancy in glomerular number and volume (a 50–75% reduction is required for clinical signs [e.g. azotaemia] to become apparent) suggests that multiple functional deficits must parallel any anatomical compromise. After characterisation of our phenotype partially supported the null hypothesis (i.e. that under conditions of normal dietary salt, increased renal sodium retention could not explain hypernatraemia in both male and female offspring of salt-loaded dams and hypertension in male offspring only) a further cohort was established in which we repeated our analyses of renal function in the offspring (at 8 weeks of age) and conducted a preliminary analysis of gastrointestinal electrolyte handling and faecal characteristics in the male and female offspring at this time
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