Maternal nutrient restriction alters renal development and blood pressure regulation of the offspring

Abstract

Studies have shown that the risk of hypertension in adulthood can be affected by the in utero environment. It is established that hypertension is linked to compromised kidney function and that factors affecting organogenesis can increase the risk of later disease. Prostaglandins (PG) and growth factors are known to play an important role in regulating kidney function and renal organogenesis. The extent, however, to which global energy restriction (where all nutrients are reduced) of the mother can programme later blood pressure control or renal PG and growth factor status is unknown. A study is described that aimed to examine the long-term effects of maternal nutrient restriction (NR) and elucidate their relationship with compromised kidney development. First, it was necessary to establish animal models. A sheep model of 50% NR during specific stages of gestation was used to investigate fetal renal development, whilst a rat model of 50% NR throughout pregnancy was used to investigate postnatal kidney development and adult functioning. Molecular analysis has shown that expression of the growth hormone-insulin-like growth factor (GH-IGF) axis is affected by NR in the fetal sheep kidneys, and that changes are dependent on the timing of NR and whether the fetus is a singleton or a twin. Analysis of the kidneys from the rat model has shown nutritional differences in the expression of PG receptors and the enzymes responsible for PG synthesis and degradation that persist into adulthood. In conclusion, NR does affect the GH-IGF and PG axes, and these changes may be important in the nutritional programming of renal functioning and adult blood pressure control.

Differential effects of maternal nutrient restriction through pregnancy on kidney development and later blood pressure control in the resulting offspring

“…In association with their smaller size in the newborn period, the kidneys of the NR animals had significantly fewer nephrons from 7 days after birth to adulthood but not at birth, which was coincident with the time at which plasma corticosterone remained at the relatively high postpartum concentrations in NR offspring, rather than falling as in controls (2). Interestingly, a similar magnitude of maternal nutrient restriction but commencing on day 13 of gestation in Wistar rats led to elevated fetal plasma corticosterone levels on day 21 of gestation and lower placental levels of 11␤-hydroxysteroid dehydrogenase type 2 mRNA (16).…”

“…At day 14, higher plasma corticosterone in postnatal NR offspring was observed (2). It is established that nephrogenesis in the fetal rat begins at 12 days of gestation and is largely complete by postnatal day 14 (35), so elevated plasma corticosterone would only inhibit this process if this occurred before this date.…”

Reduction in Maternal Circulating Ouabain Impairs Offspring Growth and Kidney Development

“…23,24 Different perturbations in the feto-maternal environment, such as a low-protein maternal diet and placental insufficiency, have been known to alter kidney weight and glomerular number and size. 25,26 Because a final wave of nephrogenesis is observed during the first week of life in the mouse, 27 kidney formation and protein activation were examined at postnatal days 17 and 21.…”

Isocaloric High-protein Diet Ameliorates Systolic Blood Pressure Increase and Cardiac Remodeling Caused by Maternal Caloric Restriction in Adult Mouse Offspring

“…Recently, Festing recommended researchers use the number of dams in developmental animal studies [19]; however, we have found significant changes of phenotype in offspring with similar animal studies in comparison based on numbers of pups [8,9,11]. We therefore used the number of pups, not dams, as the basic unit that maternal caloric restriction during pregnancy can predispose adult offspring to increased blood pressure [4], dysglycemia [5], dyslipidemia [6], and obesity [7], which correspond to cVd risk factors in humans concomitant with individual genetic and environmental backgrounds. Recently we reported a mouse animal model of maternal caloric restriction during the later half of pregnancy (30% reduction vs ad libitum feeding) where offspring developed an obesity-prone phenotype when given a high-fat diet in adulthood due partly to permanently low hypothalamic leptin sensitivity [8,9]; these findings support the concept of developmental origins of obesity in humans [10].…”