Fetal Hypoxia Results in Programming of Aberrant Angiotensin II Receptor Expression Patterns and Kidney Development

Gonzalez-Rodriguez, Pablo J.; Tong, Wenni; Qin, Xue; Li, Yong; Hu, Shirley; Zhang, Li

doi:10.7150/ijms.5566

Cited by 32 publications

(24 citation statements)

References 41 publications

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“…For example, hypoxic damage might alter the course of nephron development or vascular regulatory mechanisms, having lifelong consequences for renal blood volume regulatory mechanisms (Gonzalez‐Rodriguez et al . ). Our results suggest that blockade of NMDA receptors might be clinically useful in sparing hypoxic damage to the developing kidneys.…”

Section: Discussionmentioning

confidence: 97%

Ketamine suppresses hypoxia‐induced inflammatory responses in the late‐gestation ovine fetal kidney cortex

Chang

Zarate

Rabaglino

et al. 2015

The Journal of Physiology

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Key pointsr The fetus responds to decreases in arterial partial pressure of oxygen by redirecting the blood flow mainly to the brain and the heart, at a cost to other peripheral organs like the kidneys.r Renal hypoxia and ischaemia stimulate inflammatory and apoptotic responses. r Ketamine, an NMDA receptor antagonist, is able to reduce renal immune and inflammatory gene expressions stimulated by hypoxia.r Ketamine may have therapeutic potential for protection against ischaemic renal damage in fetuses subjected to acute hypoxia.Abstract Acute fetal hypoxia is a form of fetal stress that stimulates renal vasoconstriction and ischaemia as a consequence of the physiological redistribution of combined ventricular output. Because of the potential ischaemia-reperfusion injury to the kidney, we hypothesized that it would respond to hypoxia with an increase in the expression of inflammatory genes, and that ketamine (an N-methyl-D-aspartate receptor antagonist) would reduce or block this response. Hypoxia was induced for 30 min in chronically catheterized fetal sheep (125 ± 3 days), with or without ketamine (3 mg kg −1 ) administered intravenously to the fetus 10 min prior to hypoxia. Gene expression in fetal kidney cortex collected 24 h after the onset of hypoxia was analysed using ovine Agilent 15.5k array and validated with qPCR and immunohistochemistry in four groups of ewes: normoxic control, normoxia + ketamine, hypoxic control and hypoxia + ketamine (n = 3-4 per group). Significant differences in gene expression between groups were determined with t-statistics using the limma package for R (P ࣘ 0.05). Enriched biological processes for the 427 upregulated genes were immune and inflammatory responses and for the 946 downregulated genes were metabolic processes. Ketamine countered the effects of hypoxia on upregulated immune/inflammatory responses as well as the downregulated metabolic responses. We conclude that our transcriptomics modelling predicts that hypoxia activates inflammatory pathways and reduces metabolism in the fetal kidney cortex, and ketamine blocks or ameliorates this response. The results suggest that ketamine may have therapeutic potential for protection from ischaemic renal damage.

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Section: Discussionmentioning

confidence: 97%

Ketamine suppresses hypoxia‐induced inflammatory responses in the late‐gestation ovine fetal kidney cortex

Chang

Zarate

Rabaglino

et al. 2015

The Journal of Physiology

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“…In the presence of specific primers, the cDNA of experimental groups underwent the real-time PCR reaction (RT-PCR) using MasterMix containing SYBR green (Takara, Japan). The sequence of the primers used is given in Table 1 [14,15]. The ß-actin gene was used as the reference.…”

Section: Analysis Of Mrna Expression By Real-time Pcrmentioning

confidence: 99%

The effect of resveratrol on angiotensin II levels and the rate of transcription of its receptors in the rat cardiac hypertrophy model

et al. 2016

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This study investigated the effect of resveratrol on serum and cardiac levels of angiotensin II and transcription of its main receptors following pressure overload induced-hypertrophy. Rats were divided into untreated (Hyp) and resveratrol treated hypertrophied groups (H + R). Intact animals served as the control (Ctl). Cardiac hypertrophy was induced by abdominal aortic banding. Blood pressure (BP) was recorded via left carotid artery cannula. Fibrosis was confirmed by Masson trichrome staining. Angiotensin II level was measured using an ELIZA test. Gene expression was assessed by a real time PCR (RT-PCR) technique. We observed that in the H + R group BP and heart weight/body weight were decreased significantly (p < 0.001, p < 0.05, respectively vs Hyp). The cardiac levels of angiotensin II and AT1a mRNA were increased in the Hyp group (p < 0.01 vs Ctl). In the H + R group the AT1a mRNA level was decreased significantly (p < 0.05 vs Hyp). It could be concluded that resveratrol protects the heart against hypertrophy progression in part by affecting cardiac AT1a transcription.

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“…Decreased number of nephrons, the functional filtration units of the kidney, has been reported in several animal models of prenatal hypoxia. Rats exposed to prenatal hypoxia during the last third of pregnancy showed decreased nephron number in male and female offspring (Gonzalez-Rodriguez et al, 2013). Contrary to current literature that states nephrogenesis is complete in early postnatal life, nephron number was shown to increase almost 2-fold from P7 to 3 months of age with a nephron deficit remaining in the hypoxia-exposed offspring (GonzalezRodriguez et al, 2013).…”

Section: Effects Of Prenatal Hypoxia On the Kidneycontrasting

confidence: 48%

“…Finally, in a model of fetal hypoxia known to impair nephron endowment, while AGTR1 protein levels were unchanged during nephrogenesis, AGTR1 protein levels as well as Agtr1a and Agtr1b mRNA levels were decreased in adult offspring (Gonzalez-Rodriguez et al, 2013). It is interesting to note that, in some of the models described above, alterations to the fetal renal RAS may be protective in the short term but in the longer term are detrimental to offspring health.…”

Section: Renin-angiotensin Systemmentioning

confidence: 99%

Gestational hypoxia and programming of disease

Walton¹

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Fetal hypoxia remains the most common complication throughout pregnancy and has a wide aetiology including, but not limited to, placental insufficiency, high altitude living and maternal factors such as smoking and pulmonary disease. Intrauterine growth restriction and subsequent low birth weight are common features of pregnancies complicated by reduced oxygenation. Suboptimal organ development may arise, thereby substantially increasing vulnerability to cardiovascular and renal diseases in adulthood. Recently it has been established that prenatally programmed vulnerability to disease may be exacerbated by a postnatal 'second-hit', such as a high salt diet or ageing. The primary aim of this thesis was to investigate the effects of maternal hypoxia on the programming of cardiovascular and renal disease in mice, and secondly whether excess dietary salt intake throughout life may exacerbate disease outcomes.Pregnant CD1 mice were housed in a hypoxia chamber set to 12% oxygen throughout the last five days of pregnancy, from embryonic day (E) 14.5 until birth (P0). Control animals remained in normoxic room conditions (21% oxygen) throughout pregnancy. Upon littering, animals were removed from the hypoxia chamber and raised in normoxic room conditions. A subset of mice was fed a high salt diet from 10 weeks of age until post-mortem. Mice were housed in metabolic cages for 24 hours to assess renal function under basal conditions, and in response to a 24 hour water deprivation challenge, at 4 and 12 months of age. Blood pressure and microvascular function and structure were assessed in offspring at 12 months of age.Kidneys, hearts and aortas were collected for stereological and histological analyses.Prenatal hypoxia reduced nephron number in the kidneys of male offspring, leading to glomerular hypertrophy, renal fibrosis and mild albuminuria by 12 months of age. However, female offspring exposed to the same hypoxic insult in utero presented with normal number of glomeruli and renal pathology equivalent to control animals by 12 months of age. Both male and female hypoxia-exposed offspring had elevated mean arterial pressure at 12 months of age. A high salt diet throughout adult life increased cardiac tissue fibrosis, particularly in male hypoxia-exposed offspring, and exacerbated renal pathology in male hypoxia-exposed offspring only. Pressurized myography was performed at the time of post-mortem to assess functional, structural and mechanical properties of mesenteric resistance arteries at 12 months of age. Both male and female offspring exposed to maternal hypoxia had significantly 3 impaired endothelial function, which was not exacerbated by the high salt diet. The combination of prenatal hypoxia and a postnatal high salt diet caused marked stiffening of the microvasculature as well as loss of elastin integrity and increased collagen content in the aorta, consistent with vascular stiffness. This suggests that kidneys from female offspring are somehow protected from the in utero insult; however, this protection...

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Fetal Hypoxia Results in Programming of Aberrant Angiotensin II Receptor Expression Patterns and Kidney Development

Cited by 32 publications

References 41 publications

Ketamine suppresses hypoxia‐induced inflammatory responses in the late‐gestation ovine fetal kidney cortex

Ketamine suppresses hypoxia‐induced inflammatory responses in the late‐gestation ovine fetal kidney cortex

The effect of resveratrol on angiotensin II levels and the rate of transcription of its receptors in the rat cardiac hypertrophy model

Gestational hypoxia and programming of disease

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