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Reduction in maternal circulating ouabain impairs offspring growth and kidney development.

ABSTRACT: Ouabain, a steroid present in the circulation and in various tissues, was shown to affect the growth and viability of various cells in culture. To test for the possible influence of this steroid on growth and viability in vivo, we investigated the involvement of maternal circulating ouabain in the regulation of fetal growth and organ development. We show that intraperitoneal administration of anti-ouabain antibodies to pregnant mice resulted in a >80% decline in the circulating ouabain level. This reduction caused a significant decrease in offspring body weight, accompanied by enlargement of the offspring heart and inhibition of kidney and liver growth. Kidney growth inhibition was manifested by a decrease in the size and number of nephrons. After the reduction in maternal circulating ouabain, kidney expression of cyclin D1 was reduced and the expression of the ?1 isoform of the Na(+), K(+)-ATPase was increased. In addition, the elevation of proliferation signals including ERK1/2, p-90RSK, Akt, PCNA, and Ki-67, and a reduction in apoptotic factors such as Bax, caspase-3, and TUNEL were detected. During human pregnancy, the circulating maternal ouabain level increased and the highest concentration of the steroid was found in the placenta. Furthermore, circulating ouabain levels in women with small-for-gestational age neonates were significantly lower than the levels in women with normal-for-gestational age newborns. These results support the notion that ouabain is a growth factor and suggest that a reduction in the concentration of this hormone during pregnancy may increase the risk of impaired growth and kidney development.

SUBMITTER: Dvela-Levitt M

PROVIDER: S-EPMC4413757 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Reduction in maternal circulating ouabain impairs offspring growth and kidney development.

Dvela-Levitt Moran M Cohen-Ben Ami Hagit H Rosen Haim H Ornoy Asher A Hochner-Celnikier Drorith D Granat Menachem M Lichtstein David D

Journal of the American Society of Nephrology : JASN 20141007 5

Ouabain, a steroid present in the circulation and in various tissues, was shown to affect the growth and viability of various cells in culture. To test for the possible influence of this steroid on growth and viability in vivo, we investigated the involvement of maternal circulating ouabain in the regulation of fetal growth and organ development. We show that intraperitoneal administration of anti-ouabain antibodies to pregnant mice resulted in a >80% decline in the circulating ouabain level. Th ...[more]

PMID: 25294233

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Project description:BackgroundExcessive gestational weight gain (GWG), which is associated with adverse long-term effects on the health of the offspring, has become a major clinical problem. Accumulating evidence indicates that the ovary kisspeptin/GPR54 system directly participates in a series of physiological activities. We used a model of high-fat diet (HFD) during gestational to investigate offspring's ovarian function and whether kisspeptin/GPR54 system is involved.MethodsAfter introducing the male and confirmation of mating by checking a vaginal sperm plug, female rats were randomized into two groups: control diet called NCD group and high-fat diet called HFD group. After birth, all rats were changed into a control diet and litter size was adjusted to 12 pups per litter. Ovaries were collected for assessment at postnatal day (PND) 4 and PND 30. The timing of vaginal opening was recorded, and the estrous cyclicity was monitored for 2 consecutive weeks immediately. Primary granulosa cells and ovaries which were taken from PND 4 were collected for determination of the direct effect of kisspeptin-10 (kp-10) in vitro.ResultsNeonatal rats exposed to HFD during gestation had a lower number of secondary follicles in the ovary. The expression of follicle-stimulating hormone receptor (FSHR) and kisspeptin was not altered. At prepuberty, the number of antral follicles and preovulatory follicles was elevated with decreased type III follicles in the HFD group. While the expression of ovulation-related genes was decreased, the expression levels of follicular growth-related genes and steroidogenesis synthesis related genes were elevated. A significant increase in kiss1 mRNA and kisspeptin protein was detected without changes in kiss1r mRNA and GPR54. Maternal high-fat diet during gestation resulted in a significant advanced puberty onset and an irregular estrous cycle in offspring rats. In addition, the administration of kp-10 produced an increase in viability of primary granulosa cells and enlarged the size of oocytes.ConclusionsHFD exposure during maternal gestation had a long-term effect on reproductive function in the offspring and the increased ovarian kisspeptin/GPR54 system might be involved.

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Reduction in maternal circulating ouabain impairs offspring growth and kidney development.

Publications

Reduction in maternal circulating ouabain impairs offspring growth and kidney development.

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