Adult blood pressure profile is susceptible to prenatal programming by maternal low-protein diet in the rat. The mechanism may involve an altered renin-aldosterone axis and a deficit in total nephron number.

An experimental model of prenatal programming of hypertension in the rat, induced by a maternal low-protein diet during pregnancy, was employed to study the role of renal Na reabsorption in the pathogenesis. The abundance of the apical Na transporter type III Na/H exchanger (NHE3), bumetanide-sensitive Na-K-2Cl cotransporter (BSC1), thiazide-sensitive Na-Cl cotransporter (TSC), and the amiloridesensitive epithelial Na channel (ENaC) was determined by semiquantitative immunoblotting in kidneys from the offspring at 4 wk of age, before hypertension became manifest. There were no significant differences between the experimental and control rats in the abundance of NHE3 or any of the ENaC subunits. In contrast, the quantity of BSC1 in the experimental group was increased to 302% of control (P Ͻ 0.001) and that of TSC to 157% of control (P Ͻ 0.05). Determination of specific mRNA levels by ELISA-linked RT-PCR revealed a significantly increased BSC1 mRNA at 1 day (P Ͻ 0.01), 4 wk (P Ͻ 0.01), and 8 wk (P Ͻ 0.001) of age, and a significantly increased TSC mRNA at 4 wk of age (P Ͻ 0.05) in the experimental group. The results suggest that prenatal programming of hypertension involves transcriptional upregulation of Na transport in thick ascending limb and distal convoluted tubule. sodium transport; thick ascending limb; distal convoluted tubule; essential hypertension; pressure natriuresis; bumetanide-sensitive sodium-potassium-2 chloride cotransporter; thiazide-sensitive sodium-chloride cotransporter OVER THE PAST DECADE, CONVINCING epidemiological evidence has accumulated documenting the association of intrauterine growth retardation with essential hypertension in adulthood (2,6,7,19,22). Maternal nutrition may play an important role in the prenatal programming of hypertension (1, 17), but the fetal mechanisms involved are unclear. Both renal (3) and nonrenal (17) mechanisms have been postulated to play a role. The present study was based on the hypothesis that the fetal kidney is programmed to inappropriately retain Na in later life; the specific purpose was to examine the potential role of abnormal upregulation of Na transporters. An experimental rat model of maternal protein restriction was employed to induce hypertension in the offspring. The results show upregulation of two critical Na transporters, the thick ascending limb (TAL) bumetanide-sensitive Na-K-2Cl cotransporter (BSC1) and the distal convoluted tubule (DCT) thiazide-sensitive Na-Cl cotransporter (TSC), before and during the early phase of the development of hypertension. METHODSAnimal model. As previously described by our laboratory (20, 26), timed-pregnant Sprague-Dawley rats were placed on a 6% protein (low protein; LP) or an isocaloric 20% protein (control) diet from the gestational age of 12 days through the remainder of the pregnancy (21.5 days). We have previously shown this protocol to result in a proportionate 15-20% reduction in kidney and body weights at birth (26). After birth, the pups were nursed by their own mothers, who were on standard 20%...

Epidemiological surveys have suggested that intrauterine growth retardation is a risk factor for the development of hypertension in later life. A rat model of intrauterine growth retardation, induced by maternal low-protein diet during the second half of pregnancy, was used to study the relationship between birth weight and adult hypertension. The offspring were born at term and were allowed to nurse normally until weaned to standard chow at 4 weeks of age. They had 15% lower birth weights than control offspring, with complete catch-up growth by age 4 weeks. Both females and males developed progressively worsening hypertension beginning at 8 weeks. The 11-month survival rate was 69% versus 100% in control animals. During the early stages of the hypertension, plasma creatinine was normal, plasma sodium concentration was slightly higher than that of control animals, plasma renin activity was suppressed, and the males had mild proteinuria. Renal function remained normal throughout the 11-month observation period, but plasma renin activity gradually rose above control values. Angiotensin-converting enzyme inhibition by enalapril, begun at 8 weeks of age, was effective in completely normalizing the blood pressure, but did not totally prevent the extra mortality. Sprague-Dawley and Wistar rat strains developed equally severe hypertension after maternal protein deprivation, despite their different susceptibilities to nephrosclerosis with aging. In conclusion, maternal low-protein diet resulted in low birth weight and adult hypertension in the rat. Primary sodium retention and expanded extracellular volume may be critical factors during the development of the hypertension.

Manning. Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension. Am J Physiol Renal Physiol 287: F262-F267, 2004. First published April 20, 2004 10.1152/ajprenal.00055.2004.-Adult hypertension may be programmed by the prenatal environment in humans and in experimental animals. The potential role of the intrarenal renin-angiotensin system (RAS) in prenatally programmed hypertension was investigated. Hypertension in rat offspring was induced by maternal protein restriction during pregnancy. The offspring were studied on day 1 of life and immediately preceding the development of hypertension on day 28. ANG I and II contents were determined by radioimmunoassy. Angiotensin receptor protein and mRNA levels were quantified by immunoblotting and real-time RT-PCR, respectively. Plasma and kidney ANG I and II were unchanged in the offspring from low-protein pregnancies (LP). ANG II type 1 receptor (AT1R) protein abundance was low in the newborn LP kidney (P Ͻ 0.05) but rose above control values by 28 days of age (P Ͻ 0.05); the rise was associated with an increase in AT1R subtype A (P Ͻ 0.01), but not subtype B, mRNA level. ANG II type 2 receptor protein expression was decreased on day 1 (P Ͻ 0.05) and increased on day 28 (P Ͻ 0.05) in LP kidneys. The results show that prenatal programming of hypertension is associated with an abnormal pattern of intrarenal RAS ontogeny that may play a pathogenetic role, for instance, by constitutively altering renal hemodynamics or Na reabsorption.fetal origins of adult disease; kidney ontogeny; low-protein diet THE CONCEPT OF "PRENATAL PROGRAMMING of adult disease" refers to modulation of future adult phenotype by nongenetic environmental factors in utero. Programming of hypertension is the most extensively studied example of prenatal programming. Both epidemiological data (2,7,8,19,24) and experimental studies (18,22,36,39) have provided strong evidence that prenatal environment can modify adult blood pressure. The development of hypertension has been linked to intrauterine growth retardation in humans (1,2,7,8,19,24) and rats (18,22,36,39), suggesting a common mechanism despite species differences. In experimental animals, maternal protein (18,36,39) and calorie (38) restriction and maternal dexamethasone treatment (9, 29) have been used to program adult hypertension in offspring.The mechanisms of the development of hypertension in offspring are unclear. Although other mechanisms such as a disordered hypothalamic-pituitary-adrenal axis have been proposed (34), there is strong evidence to support a role for the kidney in the pathogenesis. Several studies have documented a deficit in the total number of nephrons in experimental programming of hypertension (17,36,39). A recent study of humans with essential hypertension also reported a decrease in the nephron count (15), consistent with the hypothesis that congenital nephron deficit has a role in essential hypertension (4). On the other hand, we reported upregulation in renal sodium (Na) transporter...

Nursing clinicians seeking to implement best practice within their professional speciality should consider some of the issues raised within this article and seek to address these issues by developing strategies to overcome them.