The Renin-Angiotensin System, High Inherent Aerobic Capacity, and Low Breast Cancer Risk
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ABSTRACT:
PROVIDER: PRJNA788552 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR17223029_1.fastq.gz | Fastqsanger.gz | |||
| SRR17223029_2.fastq.gz | Fastqsanger.gz | |||
| SRR17223030_1.fastq.gz | Fastqsanger.gz | |||
| SRR17223030_2.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Physical activity is associated with reduced breast cancer risk. Aerobic capacity, which is the ability to generate and use energy on a sustained basis, has been hypothesized as a mechanism linking physical activity and cancer. Using selectively bred rats with distinctly different inherent aerobic capacity (IAC) in concert with a well-characterized model of breast cancer, we have previously reported that high IAC is protective against chemically induced mammary carcinogenesis. The mechanism(s) by which differing IAC confers effects on cells that reside in the mammary gland is unknown. Methods: To address this knowledge gap, RNA sequence analysis was performed on skeletal muscle, uninvolved mammary gland, and mammary carcinoma from rats of low or high IAC status. Results: Investigation of effects on upstream regulators led to a focus on the role of the renin-angiotensin system (RAS) in mediating effects on downstream targets relevant to the development of breast cancer. Patterns of RAS gene expression in skeletal muscle and mammary gland of high versus low IAC were consistent with counter-regulatory RAS activity signaling promoting anti-cancer biological functions while an opposite expression pattern of these transcripts was observed in tumor tissue. Conclusions: This study found a biologically plausible heritable relationship linking mechanisms associated with aerobic capacity and the development of breast cancer. Through RNA-seq analyses, we identified AGT as a biomarker pointing to differences in the regulation of RAS as a candidate mediator linking aerobic capacity and breast cancer.
2021-12-15 | GSE190840 | GEO
Project description:LC-MS/MS Proteomics was performed to determine proteomic differences between colon adenocarcinoma (CA) tissues and patient-matched normal colon tissues, CA-derived primary cell lines and NC-derived primary cells, and between LGCA tissues and cell lines and HGCA tissues and cell lines. Biological processes which may link the renin-angiotensin system and CA were investigated, revealing enrichment of various signalling pathways that may play roles in CA onset and progression directly or via the renin-angiotensin system.
2022-08-12 | PXD024449 | Pride
Project description:High blood pressure is one of the major public health problems which causes severe disorders in several tissues including the human kidney. One of the most important signaling pathways associated with the regulation of blood pressure is the renin-angiotensin system (RAS), with its main mediator angiotensin II (ANGII). Elevated levels of circulating and intracellular ANGII and aldosterone lead to pro-fibrotic, -inflammatory and -hypertrophic milieu that causes remodelling and dysfunction in cardiovascular and renal tissues. Furthermore, ANGII has been recognized as major risk factor for the induction of apoptosis in podocytes, ultimately leading to chronic kidney disease (CKD). In the past, disease modeling of kidney-associated malignancies was extremely difficult, as the derivation of kidney originated cells is very challenging. Here we describe a differentiation protocol for reproducible differentiation of SIX2-positive urine derived renal progenitor cells (UdRPCs) into mature podocytes bearing typical foot processes. The UdRPCs-derived podocytes show the ability to execute Albumin endocytosis and the activation of the renin-angiotensin system by being responsive to ANGII stimulation. Our data reveals the ANGII dependent downregulation of NPHS1 and SYNPO, resulting in the disruption of the complex podocyte cytoskeletal architecture, as shown by immunofluorescence-based detection of α–ACTININ. In the present manuscript we confirm and propose UdRPCs as a unique cell type useful for studying nephrogenesis and associated diseases. Furthermore, the responsiveness of UdRPCs-derived podocytes to ANGII implies potential applications in nephrotoxicity studies and drug screening.
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Project description:The human placental renin-angiotensin system (RAS) genes encoding for prorenin (REN), angiotensinogen (AGT), prorenin receptor (ATP6AP2) and angiotensin II type I (AGTR1) receptor are upregulated in early gestation and affect placental development. At this time, the placental oxygen tension is at its lowest (1-3%). Some miRNAs predicted to target the RAS are downregulated in early gestation. Our hypothesis is that the low oxygen tension in early pregnancy suppresses expression of miRNAs that target the placental RAS; thus expression of these RAS genes are upregulated. Ten miRNAs predicted to target RAS mRNAs were downregulated in response to 1% vs. 20% oxygen, and six miRNAs were decreased in cells cultured in 1% vs. 5% oxygen.
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Project description:The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP), where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differently regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently unregulated genes, angiotensinogen, was validated using a in-situ hybridization. Angiotensinogen is the precursor of angiotensin II the main effector of the brain renin-angiotensin system (RAS), which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1)) antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain and ACTH release following maternal separation. AT(1) receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and identify signaling cascades, that control stress system activity in the neonate. Keywords: phenotype Litters were randomly assigned to either a maternally non-separated or 24 hour maternally separated condition. At the time of testing, all pups from a litter were sacrificed immediately by decapitation.
2010-05-16 | E-GEOD-14687 | biostudies-arrayexpress
Project description:Epidemiological studies reveal a strong link between low aerobic capacity and metabolic and cardiovascular diseases. Two-way artificial selection of rats based on low and high intrinsic exercise capacity has produced two strains that also differ in risk for metabolic syndrome (Koch LG, Britton SL. Artificial selection for intrinsic aerobic endurance running capacity in rats. Physiol Genomics 5:45-52, 2001). Here we investigated skeletal muscle characteristics and genotype-phenotype relationships behind high and low inherited aerobic exercise capacity and the link between oxygen metabolism and metabolic disease risk factors in rats derived from generation 18. This population (n=24) of high capacity runners (HCR) and low capacity runners (LCR) differed by 615% in maximal treadmill running capacity. LCR were significantly significantly heavier and had increased blood glucose, serum insulin and triglyceride concentration. HCR had higher resting metabolic rate than LCR. Capillaries/mm2 and capillary-to-fiber ratio were significantly greater in HCR rats in soleus and gastrocnemius and capillary-to-fiber ratio in extensor digitorum longus (EDL) muscle. Subsarcolemmal mitochondrial area was 96% (p<0.01) and intermyofibrillar area was 32% (p<0.05) larger in HCR soleus. Microarray results showed that 126 genes were significantly up-regulated and 113 genes were down-regulated in HCR (p<0.05). Functional clustering and unbiased correlation analysis of muscle microarray data revealed that genes up-regulated in HCR were related to mitochondria, carboxylic acid and lipid metabolism, and oxidoreductase activity. In conclusion, our data show that aerobic capacity is strongly linked to the architecture of energy transfer and corroborate the importance of oxygen metabolism as the determinant of metabolic health and complex metabolic diseases such as metabolic syndrome and type 2 diabetes. Total RNA obtained from gastrocnemius muscle was compared between rat strains of low and high inherited aerobic exercise capacity.
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Project description:Regulated endocrine specific protein 18 (Resp18), expression has been specifically located in a series of tissues and cell types however the exact cellular function is unknown. In previous studies we have showed that a targeted disruption of Resp18 in Dahl SS rats (Resp18mutant) resulted in higher blood pressure (BP), increased renal fibrosis, and decreased survival rate on a long term (6-week) 2% high salt (HS) diet treatment compared with wild type SS rats. In the current study we studied whether a short term (1 week) exposure to HS diet shows a similar effect in Resp18mutant rats. Furthermore, previously we have shown that in addition to BP phenotype Resp18mutant rats have demonstrated deteriorative kidney phenotype evident through renal fibrosis, protein urea and protein cast formation. Based on this background we conducted BP study and performed transcriptomic profiling of the kidney after one-week exposure to HS diet treatment. Through radio-telemetry procedure, we found that the systolic BP was increased in the Resp18mutant rats compared with SS rats even with short term HS diet exposure. Therefore, we sought out to investigate if there was any alteration in the transcriptomic response by HS diet treatment in the Resp18mutant rat kidneys. Using RNA sequencing approach, we found that Resp18mutant rats showed a differential expression of 25 genes of which one was an upregulation of Ren. We confirmed the upregulation of Ren and other differentially expressed genes via qRT-PCR analysis. Upon KEGG pathway enrichment we found that the Resp18mutant rat showed upregulation in the renin angiotensin system (RAAS), and renin secretion pathway. Furthermore, the renin activity is found to be higher in Resp18mutant rats serum compared with SS rats. Therefore, these observations demonstrate that upon disruption of Resp18 gene in SS rats associated with the increase in renin secretion and thus increase BP.
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Project description:The postnatal development of the mouse is characterized by a stress hyporesponsive period (SHRP), where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differently regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently unregulated genes, angiotensinogen, was validated using a in-situ hybridization. Angiotensinogen is the precursor of angiotensin II the main effector of the brain renin-angiotensin system (RAS), which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor (AT(1)) antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain and ACTH release following maternal separation. AT(1) receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and identify signaling cascades, that control stress system activity in the neonate. Keywords: phenotype
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2018-08-21 | GSE109832 | GEO