Nutrient Restriction Impairs Nephrogenesis in a Gender-Specific Manner in the Ovine Fetus

Abstract

Inadequate nutrition compromises fetal development and poses long-term health risks for the offspring, even without decreased birth weight. The present study sought to 1) establish the ontogeny of fetal renal glomerulus number (GN) in sheep and 2) evaluate the effects of 50% global nutrient restriction (NR) during early to midgestation on GN and the renin-angiotensin system in the fetal kidney. GN increased from 78 dG (68,560 Ϯ 3802) to 135 dG (586,118 Ϯ 25,792). NR increased combined kidney weight (29 Ϯ 0.6 g versus 23 Ϯ 1.1 g), whereas decreased GN relative to right kidney weight approached significance in males (26,000 Ϯ 5300 versus 39,000 Ϯ 2800 GN/g) compared with control (C) males and females. NR decreased immunoreactive angiotensin II (Ang II) type 1 receptor (AT1) in the NR kidneys at 78 dG and increased renin at 135 dG. Immunoreactive renin decreased from 78 to 135 dG. Female fetuses had more immunoreactive Ang II type 2 receptor (AT2) than male fetuses at 78 dG and males had more AT1 at 135 dG. The present study demonstrates gender-specific differences in fetal growth and development and in fetal kidney development in pregnancies affected by NR. T he American Kidney Foundation estimates the rates of chronic renal diseases are increasing rapidly, such that 20 million Americans (one in nine adults) have some form of chronic renal disease. Similarly, epidemiologic and animal studies showing a developmental origin for renal dysfunction are also increasing (1-3). This growing body of evidence clearly shows that the kidney is sensitive to perturbations of the fetal environment. Viewed in concert with factors in modern society that may collude to impair fetal nutrition, such as poverty and drug abuse, and clinical conditions, such as hyperemesis gravidarum, anorexia nervosa, and bulimia, it is clear that decreased nutrient delivery to the fetus will affect a large number of pregnancies across socioeconomic strata (4 -6).The acquisition of renal GN is a morphogenic process that reflects sensitivity to a suboptimal intrauterine environment (7,8). Reduced GN has been shown when fetal growth restriction begins early in gestation but not when the insult is restricted to late gestation (9). Interestingly, a reduction in GN following uninephrectomy during fetal life is strongly associated with increased postnatal blood pressure (10,11), whereas adult uninephrectomy is not (12). Factors that affect nephrogenesis during fetal life therefore appear to have a greater impact on blood pressure than the hypertrophic responses induced in the adult to facilitate the maintenance of filtration surface area. In accordance with this perspective, we have recently demonstrated decreased GN associated with hypertension in the male offspring of sheep NR from early to midgestation (7). From these and other studies, it is clear that although the period in which kidney development may be affected is broad, late gestation is not a part of the critical nephrogenic window in large animals such as sheep (7,9,13,14).Previous studi...

Sex differences in developmental programming models

“…The attenuation of the endothelial response to acetylcholine induced by this model was, however, present in both male and female offspring. In keeping with the predominantly male hypertensive effects of prenatal insults on development, studies have found more impaired renal function in male than in female rat offspring (Woods et al 2005, Gilbert et al 2007, Reverte et al 2011. Focusing on studies where the sexes are compared directly within the same model, it has been suggested that an anatomical basis for impaired renal function can be seen in a direct reduction of the number of nephrons in male offspring (Woods et al 2005).…”

Sex Differences in the Developmental Programming of Adult Disease

“…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 (Baserga et al, 2007b). Similarly, sex differences have also been reported in the ontogeny of gene expression in the renal RAS (Gilbert et al, 2007a). Similar to the kidney, the mammary gland undergoes discrete phases of development.…”

“…In addition, only a subset of these studies has been evaluated for sex differences. Previous work has shown male sheep and baboon fetuses are more susceptible to the effects of poor maternal nutrition (Gilbert et al, 2005a;Gilbert et al, 2006a;Gilbert et al, 2007a). Studies in sheep have shown global caloric restriction impairs nephrogenesis and alters intrarenal immunoreactive AT 1 , AT 2 and renin expression in gestational age and gender specific ways (Gilbert et al, 2007a).…”

“…As gestation progresses and the embryo becomes a fetus, the sex dimorphism of early development re-appears around mid-gestation as male fetuses become larger than age-matched females (Hindmarsh et al, 2002;Crawford et al, 1987;Parker et al, 1984). From clinical and experimental studies we know that this size difference persists to term (Hindmarsh et al, 2002;Parker et al, 1984;Gilbert et al, 2007a;Gilbert et al, 2006a). Underlying these morphological differences are specific sex related differences in endocrinology and metabolism.…”

“…While the contribution of sex to the developmental origins of disease is widely recognized, it seems sex may exert distinctly different influences during fetal and adult life. For example, while male fetuses may be more susceptible to in utero nutrient privation (Gilbert et al, 2007a), female fetuses may have increased susceptibility to gestational overnutrition (Khan et al, 2003). The reasons for this remain nebulous; however, one clue may be held in the long observed differences in growth rates exhibited by male and female fetuses in utero (Parker et al, 1984).…”