Uteroplacental insufficiency alters nephrogenesis and downregulates cyclooxygenase-2 expression in a model of IUGR with adult-onset hypertension

Abstract

Clinical and animal studies indicate that intrauterine growth restriction (IUGR) following uteroplacental insufficiency (UPI) reduces nephron number and predisposes toward renal insufficiency early in life and increased risk of adult-onset hypertension. In this study, we hypothesized that the inducible enzyme cyclooxygenase-2 (COX-2), a pivotal protein in nephrogenesis, constitutes a mechanism through which UPI and subsequent glucocorticoid overexposure can decrease nephron number. We further hypothesized that UPI downregulates the key enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts corticosterone to inert 11-dehydrocorticosterone, thereby protecting both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) from the actions of corticosterone. Following bilateral uterine ligation on the pregnant rat, UPI significantly decreased renal COX-2, 11beta-HSD2, and GR mRNA and protein levels, but upregulated expression of MR at birth. At day 21 of life, 11beta-HSD2, GR, and also MR mRNA and protein levels were downregulated. UPI did not affect blood pressures (BP) at day 21 of life but significantly increased systolic BP in both genders at day 140. We conclude that in our animal model, UPI decreases fetal COX-2 expression during a period of active nephrogenesis in the IUGR rat, which is also characterized by decreased nephron number and adult-onset hypertension.

Sex differences in the developmental origins of hypertension and cardiorenal disease

“…Sex differences at the molecular level also persist from embryonic into fetal life. Baserga et al (8) have reported that gestation in the rat cyclooxygenase-2 (COX-2) levels were higher in the female than the male kidney at day of gestation (DG) 8, although not significantly increased at DG 21. In contrast, 11␤-hydroxysteroid dehydrogenase 2 (11␤-HSD2) levels were higher in the male control kidney at DG 21.…”

“…In contrast, 11␤-hydroxysteroid dehydrogenase 2 (11␤-HSD2) levels were higher in the male control kidney at DG 21. Both of these gene products play important roles in renal function, and alterations in either could have developmental and/or functional effects in the kidney (8). We have recently shown that considerable sex differences are observed in the response to maternal nutrient restriction (MNR) between male and female baboon fetuses near term (19).…”

IUGR increases chromatin-remodeling factor Brg1 expression and binding to GR exon 1.7 promoter in newborn male rat hippocampus

“…To test these hypotheses, we used a well-characterized rat model of UPI-induced IUGR (31,33,34), which results in significantly lighter placental mass and pup body weights compared with controls (54,64). IUGR rat pups grow up to develop metabolic disorders and impaired neurodevelopment (4,8,12,39,62,79). Furthermore, circulating corticosterone and testosterone levels are elevated in male IUGR rat pups at birth and postnatal day 21 (2,3,53), suggesting a sex-specific impairment of the HPA axis.…”

Unravelling perinatal programming of the kidney

“…TO THE EDITOR: I read with great interest the paper of Baserga et al (1), which describes the effect of uterine artery ligation in the pregnant rat on fetal cyclooxygenase-2 (COX-2) expression and blood pressure. This is an important subject and the study presents interesting results, but I would like to comment on some parts of their study.…”

“…Of interest, dams after uterine artery ligation do not provide a normal lactational environment in combination with a low number of pups per litter, as this leads to a less stimulated milk production and therefore to postnatal growth restriction (9). Baserga et al (1) culled litters to six pups only, which would have been of influence on the milk quantity and/or quality. As no data on the body weight were provided, the influence of the postnatal environment on the results cannot be determined.…”