Low functional programming of renal AT2R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure

Ao, Ying; Sun, Zhaoxia; Hu, Shuangshuang; Zuo, Na; Li, Bin; Yang, Shuailong; Xia, Liping; Wu, Yong; Wang, Linlong; Zheng, He; Wang, Hui

doi:10.1016/j.taap.2015.05.007

Cited by 37 publications

(8 citation statements)

References 67 publications

(72 reference statements)

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“…A potential pathophysiologic pathway, possibly triggering this effect, appears to be that of renal developmental abnormalities caused by PCE, including glomerulosclerosis and interstitial sclerosis [21]. Glomerulosclerosis is a glomerular lesion that leads to a progressive deterioration in renal function.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Response of Adult Male Offspring Rats to Prenatal Caffeine Exposure

Mastroleon

Κορού

Pergialiotis

et al. 2020

Cureus

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Caffeine is the most widely consumed psychoactive substance, with recommendations from health associations and regulatory bodies for limiting caffeine consumption during pregnancy being increasingly common. Prenatal exposure to caffeine has been shown to increase the risk of developing abnormalities in lipid metabolism in adult life. We further investigated the effect of prenatal caffeine exposure (PCE) (20 mg/kg of body weight) on the metabolic "reserve" of male Sprague Dawley offspring fed on a high fructose diet in adult life. Male adult PCE offspring were assigned to four groups; Nw and Nf: offspring of control mothers (N group of mothers), having received tap water or high fructose water respectively; Cw and Cf: offspring exposed to caffeine during gestation (C group of mothers) and receiving tap water or a high fructose water solution, respectively. Cf rats presented increased serum triglyceride level, as well as raised systolic and diastolic blood pressure levels, together with extensive renal tissue oedema in adulthood, compared to the other groups (p<0.05 for all comparisons). These findings show further evidence for potential detrimental metabolic effects of prenatal caffeine exposure during adulthood in this animal model.

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Section: Discussionmentioning

confidence: 99%

Metabolic Response of Adult Male Offspring Rats to Prenatal Caffeine Exposure

Mastroleon

Κορού

Pergialiotis

et al. 2020

Cureus

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“… 23 However, most organs exhibit functional development inhibition, such as the inhibition of the matrix synthesis of articular cartilage in fetuses and enhanced susceptibility to osteoarthritis in adults, 40 inhibition of steroid synthesis of the adrenal gland in fetuses and enhanced susceptibility to hyperadrenocorticism in adults, 19 and podocyte dysplasia of kidneys in fetuses and enhanced susceptibility to glomerulosclerosis in adults. 41 High intrauterine glucocorticoid levels bring about fetal multi-organ structural and functional abnormities through regulating a series of neuroendocrine developmental programs. 42 , 43 …”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid mediates prenatal caffeine exposure-induced endochondral ossification retardation and its molecular mechanism in female fetal rats

et al. 2017

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Our previous studies discovered that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) and long-bone dysplasia in offspring rats, accompanied by maternal glucocorticoid over-exposure. This study is to explore whether intrauterine high glucocorticoid level can cause endochondral ossification retardation and clarify its molecular mechanism in PCE fetal rats. Pregnant Wistar rats were intragastrically administered 30 and 120 mg/kg day of caffeine during gestational days (GDs) 9–20, then collected fetal serum and femurs at GD20. In vitro, primary chondrocytes were treated with corticosterone (0–1250 nM), caffeine (0–100 μM), mitogen-inducible gene 6 (Mig-6) siRNA and epidermal growth factor receptor (EGFR) siRNA, respectively, or together. Results showed that the hypertrophic chondrocytes zone (HZ) of PCE fetal femur was widened. Meanwhile, the expression levels of chondrocytes terminal differentiation genes in the HZ were decreased, and the chondrocytes apoptosis rate in the HZ was decreased too. Furthermore, PCE upregulated Mig-6 and suppressed EGFR expression in the HZ. In vitro, a high-concentration corticosterone (1250 nM) upregulated Mig-6 expression, inhibit EGFR/c-Jun N-terminal kinase (JNK) signaling pathway and terminal differentiation genes expression in chondrocytes and reduced cell apoptosis, and these above alterations could be partly reversed step-by-step after Mig-6 and EGFR knockdown. However, caffeine concentration dependently increased chondrocyte apoptosis without significant changes in the expression of terminal differentiation genes. Collectively, PCE caused endochondral ossification retardation in the female fetal rats, and its main mechanism was associated with glucocorticoid (rather than caffeine)-mediated chondrocyte terminal differentiation suppression by the upregulation of Mig-6 and then inhibition of EGFR/JNK pathway-mediated chondrocyte apoptosis.

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“…Our previous studies have confirmed that with overexposure to maternal GCs induced by PCE, multiple organs of fetal rats appeared to be structurally and functionally different during development. The liver, as one of those important organs, had enhanced TG synthesis (10), whereas secondary organs (e.g., articular cartilage and kidney) exhibited varying degrees of developmental inhibition and dysfunction (43,54). In this study, we confirmed that the liver had enhanced cholesterol synthesis function under high levels of maternal GCs, which is the specific manifestation of the thrifty phenotype in the fetal liver and constitutes the pathophysiological basis of susceptibility to hypercholesterolemia and related metabolic diseases in adult offspring.…”

Section: Maternal Gc Overexposure Induced Programming Alterations In mentioning

confidence: 99%

Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine‐exposed female adult rat offspring

Luo

et al. 2018

FASEB j.

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Clinical and animal studies have indicated that hypercholesterolemia and its associated diseases have intrauterine developmental origins. Our previous studies showed that prenatal caffeine exposure (PCE) led to fetal overexposure to maternal glucocorticoids (GCs) and increased serum total cholesterol levels in adult rat offspring. This study further confirms the intrauterine programming of PCE-induced hypercholesterolemia in female adult rat offspring. Pregnant Wistar rats were intragastrically administered caffeine (30, 60, and 120 mg/kg/d) from gestational day (GD)9 to 20. Female rat offspring were euthanized at GD20 and postnatal wk 12; several adult rat offspring were additionally subjected to ice-water swimming stimulation to induce chronic stress prior to death. The effects of GCs on cholesterol metabolism and epigenetic regulation were verified using the L02 cell line. The results showed that PCE induced hypercholesterolemia in adult offspring, which manifested as significantly higher levels of serum total cholesterol and LDL cholesterol (LDL-C) as well as higher ratios of LDL-C/HDL cholesterol. We further found that the cholesterol levels were increased in fetal livers but were decreased in fetal blood, accompanied by increased maternal blood cholesterol levels and reduced placental cholesterol transport. Furthermore, analysis of PCE offspring in the uterus and in a postnatal basal/chronic stress state and the results of in vitro experiments showed that hepatic cholesterol metabolism underwent GC-dependent changes and was associated with cholesterol synthase via abnormalities in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) histone acetylation. We concluded that, to compensate for intrauterine placentally derived decreases in fetal blood cholesterol levels, high intrauterine GC levels activated fetal hepatic CCAAT enhancer binding protein α signaling and down-regulated Sirtuin1 expression, which mediated the high levels of histone acetylation ( via H3K9ac and H3K14ac) and expression of HMGCR. This GC-dependent cholesterol metabolism programming effect was sustained through adulthood, leading to the occurrence of hypercholesterolemia.-Xu, D., Luo, H. W., Hu, W., Hu, S. W., Yuan, C., Wang, G. H., Zhang, L., Yu, H., Magdalou, J., Chen, L. B., Wang, H. Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine-exposed female adult rat offspring.

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Low functional programming of renal AT2R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal caffeine exposure

Cited by 37 publications

References 67 publications

Metabolic Response of Adult Male Offspring Rats to Prenatal Caffeine Exposure

Metabolic Response of Adult Male Offspring Rats to Prenatal Caffeine Exposure

Glucocorticoid mediates prenatal caffeine exposure-induced endochondral ossification retardation and its molecular mechanism in female fetal rats

Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine‐exposed female adult rat offspring

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