Analysis of altered mRNA expression profiles in the genetic hypercalciuric stone-forming (GHS) rat compared to normal SD rat
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE75542 | GEO | 2015/12/01
SECONDARY ACCESSION(S): PRJNA304507
REPOSITORIES: GEO
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Project description:Urolithiasis is a common disease to human beings, and idiopathic hypercalciuria (IH) is an important risk factor of calcium urolithiasis, previous studies strongly suggested that the decreased tubular Ca2+ reabsorption played a key role of hypercalciuria. However,the molecular mechanism of IH-urolithiasis formation is still not completely elucidated. GHS rat is regarded as an ideal animal model of calcium urolithiasis, reveals many identical pathophysiologic characteristics with IH patients . We analyzed miRNA expression profiles of the kidney of GHS rat in order to find out the target genes and signaling pathways in the pathogenesis of IH.
2015-12-01 | GSE75541 | GEO
Project description:miRNA and mRNA profiles in the genetic hypercalciuric stone-forming (GHS) rat compared to normal SD rat
| PRJNA304503 | ENA
Project description:Background. MicroRNAs (miRNAs) influence a variety of biological functions by regulating gene expression post-transcriptionally. Aberrant miRNA expression has been associated with many human diseases. Urolithiasis is a common disease, and idiopathic hypercalciuria (IH) is an important risk factor for calcium urolithiasis. However, miRNA expression patterns and their biological functions in urolithiasis remain unknown. Methods and Results. A multi-step approach combining microarray miRNA and mRNA expression profile and bioinformatics analysis was adopted to analyze dysregulated miRNAs and genes in genetic hypercalciuric stone-forming (GHS) rat kidneys, using normal Sprague-Dawley (SD) rats as controls. We identified 2418 mRNAs and 19 miRNAs as significantly differentially expressed, over 700 gene ontology (GO) terms and 83 KEGG pathways that were significantly enriched in GHS rats. In addition, we constructed an miRNA-gene network that suggested that rno-miR-674-5p, rno-miR-672-5p, rno-miR-138-5p and rno-miR-21-3p may play important roles in the regulatory network. Furthermore, signal-net analysis suggested that NF-kappa B likely plays a crucial role in hypercalciuria urolithiasis. Conclusions. This study presents a global view of mRNA and miRNA expression in GHS rat kidneys, and suggests that miRNAs may be important in the regulation of hypercalciuria. The data provide valuable insights for future research, which should aim at validating the role of the genes featured here in the pathophysiology of hypercalciuria.
| S-EPMC4824905 | biostudies-literature
Project description:Rational & objectiveDiabetes and uric acid kidney stones are strongly associated. Patients with calcium kidney stones also have higher risk of developing diabetes compared with nonkidney stone patients yet this has not been further investigated. We aimed to characterize insulin resistance in calcium kidney stone patients.Study designObservational.Setting & populationThis study was performed in the University of Chicago Clinical Research Center. Kidney stone patients (N = 42) were selected for having idiopathic hypercalciuria and calcium stones with no other medical conditions, and controls (N = 27) were healthy.ExposuresAll participants presented to the Clinical Research Center in a fasting state and at least 2 timed fasting blood and urine collections were collected before a fixed breakfast. Six additional timed blood and urine collections were performed after breakfast.OutcomesWe compared fasting and fed indices of insulin resistance between the groups.Analytic approachWe used t tests and multivariable linear regression models. A sensitivity analysis removing all patients who had ever been on a thiazide diuretic was also performed.ResultsIn separate multivariable linear models, kidney stone patients had higher fasting serum insulin levels (24 (3-46 pmol/L), P = 0.03) and higher homeostatic model of insulin resistance (HOMA-IR) (1.0 (0.2-1.8), P = 0.02). In separate multivariable linear models, kidney stone patients had higher fed serum glucose levels (10 (2-18 mg/dL), P = 0.01). Results were similar in a sensitivity analysis removing all patients who had ever been on a thiazide diuretic. There were no differences in urine composition based on HOMA-IR levels.LimitationsSingle institution. Small sample size limited subanalyses by different calcium stone types.ConclusionsCalcium kidney stone patients without diabetes or other medical conditions demonstrated signs of insulin resistance compared with healthy matched controls.
| S-EPMC11615144 | biostudies-literature
Project description:Aims Ischemic cardiomyopathy with comorbid sleep apnea syndrome (SAS) is associated with worse long-term outcomes. Intermittent hypoxia (IH), a key feature of SAS, exacerbates sympathetic activity, hastening cardiac dysfunction and remodeling in ischemic cardiomyopathy rat models. This study explores whether targeted cardiac sympathetic denervation (CSD) can limit IH-induced progression of ischemic cardiomyopathy. Methods and results Male Wistar rats underwent myocardial infarction (MI) via permanent left coronary artery ligation, and CSD was simultaneously achieved through ablation of the left middle cervical and stellate ganglions. Rats were exposed to IH (21–5% fraction of inspired O2, 60 s cycle, 8 h/day) or normoxia (N) for 14 weeks starting 3 days post-surgery. Throughout the intervention period, cardiac sympathetic activity was assessed using spectral analysis of heart rate variability (HRV) from vigil ECG collected with a specialized jacket. Cardiac function and remodeling were monitored via echocardiography. Additionally, isolated cardiomyocytes from rats exposed to IH or N for 6 weeks were assessed for calcium transient, sarcomere shortening and adrenergic reserve using isoproterenol stimulation (100 nM). CSD reduced cardiac sympathetic activity and prevented IH-induced blunting of cardiomyocyte response to isoproterenol challenge. In hypoxic animals, CSD reduced alterations in long-term ejection fraction and mitigated cardiomyocyte hypertrophy. Transcriptomic analysis unveiled that CSD triggered biological processes related to cardiac repair and regeneration. Immunohistochemistry further supported these findings, demonstrating increased cardiomyocyte proliferation in the hypoxic group, as indicated by elevated Ki67 expression colocalized with MF20 markers. Conclusions Our data demonstrate that cardiac sympathetic denervation prevents IH-induced depletion of cardiac adrenergic reserve and deterioration of cardiac function in a rat model of ischemic cardiomyopathy. This study questions the role of sympathetic activity and hypoxia in cardiac regeneration and on the optimal management of sympathetic hyperactivity in ischemic cardiomyopathy in the specific context of associated SAS.
2025-03-28 | GSE262637 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2015-12-01 | GSE75543 | GEO
Project description:The long-term effects of neonatal intermittent hypoxia (IH), an accepted model of apnea-induced hypoxia, are unclear. We have previously shown lasting “programming” effects on the HPA axis in adult rats exposed to neonatal IH. We hypothesized that neonatal rat exposure to IH will subsequently result in a heightened inflammatory state in the adult. Rat pups were exposed to normoxia (control) or six cycles of 5% IH or 10% IH over one hour daily from postnatal day 2 – 6. Plasma samples from blood obtained at 114 days of age were analyzed by assessing the capacity to induce transcription in a healthy peripheral blood mononuclear cell (PBMC) population and read using a high-density microarray. The analysis of plasma from adult rats previously exposed to neonatal 5% IH vs. 10% IH resulted in 2,579 significantly regulated genes including increased expression of Cxcl1, Cxcl2, Ccl3, Il1a, and Il1b. We conclude that neonatal exposure to intermittent hypoxia elicits a long-lasting programming effect in the adult resulting in an upregulation of inflammatory-related genes. Apnea is the most common cause of neonatal hypoxia affecting about 50% of preterm births (30 – 31 weeks), usually due to immature respiratory development. Upregulation of inflammatory genes and pathways in children 7 – 10 years of age has been shown, and there is a known increased risk of insulin resistance in adulthood when the fetus is exposed to maternal hypoxia, but the mechanism is unclear. The long-term metabolic, endocrine, and immunological effects of neonatal intermittent hypoxia (IH) exposure, an accepted model of apnea-induced hypoxia, have not been thoroughly evaluated. Recent studies in rats have shown that perinatal IH exposure can result in oxidative stress, causing a permanent immune response subsequently resulting in features of diabetes mellitus. We have previously examined adult rats exposed to neonatal intermittent hypoxia and perinatal continuous hypoxia, and have found lasting “programming” effects on the HPA axis. We now assess the long term effects of an accepted model of apnea-induced hypoxia using a validated transcriptional bioassay to study the extracellular milieu of adult rats exposed to neonatal intermittent hypoxia. We hypothesize that exposure to neonatal intermittent hypoxia will result in an increased inflammatory state in the adult as a result of long-lasting programming.
2016-01-07 | GSE74145 | GEO
Project description:The long-term effects of neonatal intermittent hypoxia (IH), an accepted model of apnea-induced hypoxia, are unclear. We have previously shown lasting âprogrammingâ effects on the HPA axis in adult rats exposed to neonatal IH. We hypothesized that neonatal rat exposure to IH will subsequently result in a heightened inflammatory state in the adult. Rat pups were exposed to normoxia (control) or six cycles of 5% IH or 10% IH over one hour daily from postnatal day 2 â 6. Plasma samples from blood obtained at 114 days of age were analyzed by assessing the capacity to induce transcription in a healthy peripheral blood mononuclear cell (PBMC) population and read using a high-density microarray. The analysis of plasma from adult rats previously exposed to neonatal 5% IH vs. 10% IH resulted in 2,579 significantly regulated genes including increased expression of Cxcl1, Cxcl2, Ccl3, Il1a, and Il1b. We conclude that neonatal exposure to intermittent hypoxia elicits a long-lasting programming effect in the adult resulting in an upregulation of inflammatory-related genes. Apnea is the most common cause of neonatal hypoxia affecting about 50% of preterm births (30 â 31 weeks), usually due to immature respiratory development. Upregulation of inflammatory genes and pathways in children 7 â 10 years of age has been shown, and there is a known increased risk of insulin resistance in adulthood when the fetus is exposed to maternal hypoxia, but the mechanism is unclear. The long-term metabolic, endocrine, and immunological effects of neonatal intermittent hypoxia (IH) exposure, an accepted model of apnea-induced hypoxia, have not been thoroughly evaluated. Recent studies in rats have shown that perinatal IH exposure can result in oxidative stress, causing a permanent immune response subsequently resulting in features of diabetes mellitus. We have previously examined adult rats exposed to neonatal intermittent hypoxia and perinatal continuous hypoxia, and have found lasting âÂÂprogrammingâ effects on the HPA axis. We now assess the long term effects of an accepted model of apnea-induced hypoxia using a validated transcriptional bioassay to study the extracellular milieu of adult rats exposed to neonatal intermittent hypoxia. We hypothesize that exposure to neonatal intermittent hypoxia will result in an increased inflammatory state in the adult as a result of long-lasting programming. Sprague-Dawley (SD) rat pups were treated with neonatal normoxia (21% O2, control), 5% intermittent hypoxia (IH), or 10% IH on postnatal days (PD) 2-6, daily over 1 hr. They were reared normally by birth dams and weaned at PD22. Males were allowed to mature and sacrificed at age PD114 after an overnight fast. Whole blood collected by decapitation into tubes with EDTA, and plasma saved for further analysis. Two adult (~180 day) male Brown Norway (BN) rats served as PBMC donors. Cells were incubated with 20% plasma that was either autologous BN (self-control), or one of 3 pools: a) SD normoxic N=8, b) SD 5% IH treated N=5, and c) SD 10% IH N=3.
2016-01-07 | E-GEOD-74145 | biostudies-arrayexpress
Project description:Human idiopathic hypercalciuria (IH) is the most common cause of calcium oxalate nephrolithiasis with perturbed calcium metabolism with increased bone resorption and decreased renal calcium reabsorption, which can be phenotype-copied in the genetic hypercalciuric stone-forming (GHS) rat model. We previously demonstrated that high VDR expression plays important roles in the development of hypercalciuria in the GHS rats. However, the underlying mechanism through which VDR impact hypercalciuria development remains to be fully understood. Here, we sought to determine how VDR regulated its target genes that are implicated in calcium homeostasis and potentially hypercalciuria. We found that VDR expression in the GHS rats was elevated in the calcium transporting tissues, as well as in the thymus and prostate, but not in lung, brain, heart, liver and spleen, when compared with control SD rats. Snail expression in the GHS rats was significantly downregulated in kidney, intestine, thymus and testis. Intraperitoneal injection of 1,25(OH)2D3 significantly upregulated the expression of renal calcium sensing receptor (CaSR), intestinal calcium transporters transient receptor potential vanilloid type 6 (TRPV6), and VDR in GHS rats, compared with that in control SD rats. ChIP assays revealed that VDR specifically bound to the proximal promoters of target genes, followed by histone H3 hyperacetylation or hypermethylation. Collectively, our results suggest that elevated VDR expression may contribute to the development of hypercalciuria by sensitizing VDR target genes to 1,25(OH)2D3 through histone modifications at their promoter regions in a genetic hypercalciuric stone-forming (GHS) rat model.
| S-EPMC9243318 | biostudies-literature
Project description:Patients with idiopathic hypercalciuria (IH) and genetic hypercalciuric stone-forming (GHS) rats, an animal model of IH, are both characterized by normal serum Ca, hypercalciuria, Ca nephrolithiasis, reduced renal Ca reabsorption, and increased bone resorption. Serum 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels are elevated or normal in IH and are normal in GHS rats. In GHS rats, vitamin D receptor (VDR) protein levels are elevated in intestinal, kidney, and bone cells, and in IH, peripheral blood monocyte VDR levels are high. The high VDR is thought to amplify the target-tissue actions of normal circulating 1,25(OH)(2)D levels to increase Ca transport. The aim of this study was to elucidate the molecular mechanisms whereby Snail may contribute to the high VDR levels in GHS rats. In the study, Snail gene expression and protein levels were lower in GHS rat tissues and inversely correlated with VDR gene expression and protein levels in intestine and kidney cells. In human kidney and colon cell lines, ChIP assays revealed endogenous Snail binding close to specific E-box sequences within the human VDR promoter region, whereas only one E-box specifically bound Snail in the rat promoter. Snail binding to rat VDR promoter E-box regions was reduced in GHS compared with normal control intestine and was accompanied by hyperacetylation of histone H(3). These results provide evidence that elevated VDR in GHS rats likely occurs because of derepression resulting from reduced Snail binding to the VDR promoter and hyperacetylation of histone H(3).
| S-EPMC3153334 | biostudies-literature