Uteroplacental insufficiency temporally exacerbates salt-induced hypertension associated with a reduced natriuretic response in male rat offspring

Abstract

Low weight at birth increases the risk of developing chronic diseases in adulthood A diet that is high in salt is known to elevate blood pressure, which is a major risk factor for cardiovascular and kidney diseases The present study demonstrates that growth restricted male rats have a heightened sensitivity to high dietary salt, in the context of raised systolic blood pressure, reduced urinary sodium excretion and stiffer mesenteric resistance vessels Other salt-induced effects, such as kidney hyperfiltration, albuminuria and glomerular damage, were not exacerbated by being born small The present study demonstrates that male offspring born small have an increased cardiovascular susceptibility to high dietary salt, such that that minimizing salt intake is probably of particular benefit to this at-risk population ABSTRACT: Intrauterine growth restriction increases the risk of developing chronic diseases in adulthood. Lifestyle factors, such as poor dietary choices, may elevate this risk. We determined whether being born small increases the sensitivity to a dietary salt challenge, in the context of hypertension, kidney disease and arterial stiffness. Bilateral uterine vessel ligation or sham surgery (offspring termed Restricted and Control, respectively) was performed on 18-day pregnant Wistar Kyoto rats. Male offspring were allocated to receive a diet high in salt (8% sodium chloride) or remain on standard rat chow (0.52% sodium chloride) from 20 to 26 weeks of age for 6 weeks. Systolic blood pressure (tail-cuff), renal function (24 h urine excretions) and vascular stiffness (pressure myography) were assessed. Restricted males were born 15% lighter than Controls and remained smaller throughout the study. Salt-induced hypertension was exacerbated in Restricted offspring, reaching a peak systolic pressure of ∼175 mmHg earlier than normal weight counterparts. The natriuretic response to high dietary salt in Restricted animals was less than in Controls and may explain the early rise in arterial pressure. Growth restricted males allocated to a high salt diet also had increased passive arterial stiffness of mesenteric resistance arteries. Other aspects of renal function, including salt-induced hyperfiltration, albuminuria and glomerular damage, were not exacerbated by uteroplacental insufficiency. The present study demonstrates that male offspring exposed to uteroplacental insufficiency and born small have an increased sensitivity to salt-induced hypertension and arterial remodelling.

Keywords: blood pressure; developmental programming; growth restriction.

Figure 1. Systolic blood pressure during 6 weeks of a high salt diet

Systolic blood pressure in (A) normal salt diet (0.52%) and (B) high salt diet (8%) groups at baseline (20 weeks of age), 3 weeks (23 weeks of age) and 6 weeks (26 weeks of age) of diet intervention and (C) all groups at 3 weeks (23 weeks of age) and (D) 6 weeks (26 weeks of age) of diet intervention. Data in (A) and (B) are the mean ± SEM; n = 7–11 per group or individual values (C and D) with the mean ± SEM. ^* P < 0.05, ^** P < 0.01 Restricted vs. Control within diet group by Fisher's LSD test. A and B, continuous lines indicate P < 0.05 between connecting time‐points and dotted lines indicate no significance between connecting time‐points. UPI, uteroplacental insufficiency; NS, not significant.

Figure 2. Fluid and electrolyte balance following 6 weeks of a high salt diet

Water intake in relation to urinary ouput (A and B), predicted filtered sodium (C), urinary sodium excretion (U_NaV) (D), fractional sodium excretion (FE_Na) (E), urinary potassium excretion (U_KV) (F) and sodium to potassium ratio (U_Na:KV) (G) following 6 weeks of diet intervention (26 weeks of age). Data are individual values with the mean ± SEM. Pearson's correlation performed for (A). ^* P < 0.05, ^** P < 0.01 Restricted vs. Control within diet group by Fisher's LSD test. UPI, uteroplacental insufficiency; NS, not significant.

Figure 3. Kidney function and histopathology following 6 weeks of a high salt diet

Creatinine clearance (A), albuminuria (B and C), proteinuria (D), glomerulosclerosis (E), tubulointerstitial fibrosis (F) and perivascular fibrosis (G) following 6 weeks of diet intervention (26 weeks of age). Data are individual values with the mean ± SEM. ^* P < 0.05, ^** P < 0.01 Restricted vs. Control within diet group by Fisher's LSD test. UPI, uteroplacental insufficiency; NS, not significant. Representative kidney sections stained with PAS and Masson's trichrome. Scale bars = 50 μm.

Figure 4. Passive mechanical wall properties of mesenteric and renal arteries following 6 weeks of a high salt diet

Stress–strain relationships (A and C) and media‐to‐lumen ratio (B and D) for mesenteric (top) and renal (bottom) arteries following 6 weeks of diet intervention (26 weeks of age). Data are the mean ± SEM; n = 10–11 per group. #P < 0.05 High vs. Normal salt within uteroplacental insufficiency group by Tukey's post hoc test.