Nitrite Protects Against Cardiac Surgery-Associated AKI via Inflammation Suppression: Insights from a Rat CPB Model
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ABSTRACT:
PROVIDER: PRJNA1226089 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32410817_1.fastq.gz | Fastqsanger.gz | |||
| SRR32410817_2.fastq.gz | Fastqsanger.gz | |||
| SRR32410818_1.fastq.gz | Fastqsanger.gz | |||
| SRR32410818_2.fastq.gz | Fastqsanger.gz | |||
| SRR32410819_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Cardiac surgery-associated acute kidney injury (CS-AKI) is reported in 20-30% of patients undergoing cardiac surgery and, leading to poor outcomes and increased healthcare costs. Because the pathophysiology of CS-AKI is complex and has not been fully elucidated, no effective preventive and interventional strategy has been reported. Nitrite, a nitric oxide (NO) donor under hypoxic conditions, has shown to exert organ-protective effects in various kind of preclinical models, however, its efficacy in CS-AKI remains unclear. Objectives: This study aimed to generate a rat cardiopulmonary bypass (CPB) model to induce AKI, identify key molecular pathways involved in its pathophysiology, and evaluate the renoprotective effects of nitrite. Methods: A CPB model was established using rats and AKI was confirmed through molecular and histological analysis. RNA-seq was performed to identify differentially expressed genes and enriched pathway. Nitrite (2 mg/kg) was intravenously administered prior to CPB, and its effects on kidney injury markers and inflammation-related pathways were evaluated. Results: AKI was successfully produced in our rat CPB model, as evidenced by increased KIM-1 and NGAL expression and renal histological damage. RNA-seq revealed significant activation of multiple inflammation-related pathways, including TNF and NFκB signaling pathway. Nitrite administration significantly reduced KIM-1 and NGAL expression and suppressed these pathways associated with development of AKI. Conclusion: This study underscores the role of inflammation in CS-AKI pathophysiology and demonstrates the renoprotective potential of nitrite. These findings provide a foundation for further investigations into nitrite's mechanisms and its potential clinical application in cardiac surgery.
2025-03-01 | GSE290044 | GEO
Project description:Acute kidney Injury (AKI) following open-heart surgery with cardiopulmonary bypass (CPB) is associated with an increased morbidity and mortality. The goal of this study is to explore patterns of gene expression in human AKI following CPB. This prospective observational study was approved by the Institutional Review Board Human Subjects Committee. Design and methods: Peripheral blood RNA samples were collected prospectively from a cohort of 30 patients at Caritas St. Elizabeths Medical Center in Boston, MA, undergoing CPB at time points immediately prior, and two and 24 hours following CPB. Gene expression patterns of four patients who developed AKI (cases) following CPB will be compared with six patients matched for clinical characteristics, who did not develop AKI (controls). AKI was defined by an incremental increase in serum creatinine of 30% within 72 hours following CPB. For peripheral blood RNA sampling, 2.5 ml of venous whole blood was collected into PAXgene Blood RNA Tube collection tubes (PreAnalytiX GmbH, Hombrechtikon, CH). Whole blood RNA was extracted with the PAXgene Blood RNA extraction Kit according to the manufacturers instructions (PAXgene RNA Kit Handbook, 06/2005). All biological samples are stored at 80° C.
2009-12-12 | E-TABM-595 | biostudies-arrayexpress
Project description:In an effort to identify novel biomarkers capable of predicting the development of acute kidney injury (AKI) after cardiac surgery with cardiopulmonary bypass (CPB) use, urine specimens were collected before and at 4 and 24 hours after surgery from 106 patients and analyzed by means of nuclear magnetic resonance (NMR) spectroscopy and machine learning methods.
2012-10-21 | MTBLS24 | MetaboLights
Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.
2013-09-05 | E-GEOD-44925 | biostudies-arrayexpress
Project description:Ischemic acute kidney injury (AKI), a complication that frequently occurs in hospital settings, is often associated with hemodynamic compromise, sepsis, cardiac surgery or exposure to nephrotoxicants. AKI is associated with immune cell infiltration into the kidney stroma, which causes acute tubular injury. Here, using a murine renal ischemic-reperfusion injury (IRI) model we show that intercalated cells (ICs) rapidly adopt a pro-inflammatory phenotype post IRI. During the early phase of AKI, we demonstrate that either blocking the pro-inflammatory P2Y14 receptor located on the apical membrane of ICs, or ablation of the gene encoding the P2Y14 receptor in ICs: 1) inhibits IRI-induced chemokine expression increase in ICs; 2) reduces neutrophil and monocyte renal infiltration; 3) reduces the extent of kidney dysfunction; and 4) attenuates proximal tubule (PT) damage. These observations indicate that the P2Y14 receptor participates in the very first inflammatory steps associated with ischemic AKI. In addition, we show that the concentration of the P2Y14 receptor ligand, uridine diphosphate-glucose (UDP-Glc), is higher in urine samples from intensive care unit patients who developed AKI when compared with urine from patients without AKI. In particular, we observed a strong correlation between UDP-Glc concentration and the development of AKI in cardiac surgery patients. Our study identifies the UDP-Glc/P2Y14 receptor axis as a potential target for the prevention and/or attenuation of ischemic-AKI.
2020-03-17 | GSE144522 | GEO
Project description:Farnesoid X receptor (FXR, also known as NR1H4) is crucial to nephroprotective in several kinds of kidney diseases, including obesity, diabetes, aging, acute kidney injury and chronic kidney disease. FXR plays a key role in maintaining cholesterol and bile acid levels and is highly expressed in the liver, intestine and kidneys. In kidney diseases, it is reported that FXR has anti-lipogenic, anti‐inflammatory, antifibrotic, and antioxidant functions. Here, using genomics analysis, we investigated whether FXR attenuates cisplatin-induced AKI through the regulation of ferroptosis. The increased blood urea nitrogen, serum creatinine and ferroptotic responses in cisplatin-induced AKI mice were attenuated by treatment with FXR agonist, GW4064, while those were exacerbated in FXR knockout mice. Using RNA-sequencing analysis, we found novel target genes for FXR associated with ferroptosis. FXR agonist treatment increases lipid and glutathione metabolic gene expression and decreases cell death genes expression. This study identifies transcriptional regulation of ferroptosis by FXR as a potential therapeutic target for cisplatin-induced AKI.
2022-07-06 | GSE193860 | GEO
Project description:Objectives: Secretion of extracellular vesicles (EV) and associated micro-RNAs (miR) is altered during cellular stress and may serve as biomarkers of organ injury. We hypothesized that measuring changes in urinary levels of EV and miR will predict the onset of acute kidney injury in cardiac surgery patients. Design: Predictive accuracy biomarker study performed in the cohort of the REVAKI-2 trial Setting: Single center ICU between September 2015 and September 2018 Interventions: Intravenous sildenafil citrate 12.5 mg kg-1 over 150 min or dextrose 5% at the commencement of surgery. Measurements and main results: Urine samples were collected before and 24 hours after the procedure from 93 cardiac surgery patients. Urine EV concentrations and size distribution were assessed using NanoSight. EV derivation and levels were measured using flow cytometry. Samples from 10 selected patients were sequenced to detect differentially expressed miR. Verification was performed with advanced TaqMan assays in samples from all patients. Urine EV concentrations significantly increased in patients with AKI after surgery, with the percentage of EV positive for aquaporin-2 and β1-integrin also increasing. Pre surgery podocalyxin-positive EV were significantly lower, and β1-integrin EV werehigher in patients with AKI. The levels of the former correlated with the severity of theinjury. miR-125a-5p was expressed at higher levels in urine from patients with AKI stage 2/3. Levels of miR-10a-5p decreased after surgery in AKI patients; its levels correlated with the severity of the injury. Preoperative levels of podocalyxin EVs and miR-125a-5p had moderate AKI predictive value and, in a logistic model together with ICU lactate levels, offered good (AUC = 80.9%) AKI prediction. Conclusions: Lower levels of podocalyxin-positive EV at baseline predict the severity of post-surgery AKI. Urine EV concentrations and miR expression offer excellent predictive accuracy when combined with commonly measured biomarkers.
2022-02-26 | GSE197272 | GEO
Project description:Tetralogy of Fallot (ToF) and Atrial Septal Defects (ASD) are the most common types of congenital heart disease and a major cause of childhood morbidity and mortality. Cardiopulmonary bypass (CPB) is used during corrective cardiac surgery to support circulation and heart stabilization. However, this technique triggers systemic inflammatory and stress response and consequent increased risk of postoperative complications. The aim of this study was to define the molecular bases of ToF and ASD pathogenesis and response to CPB and identify new specific biomarkers. We conducted comparative transcriptome analysis of right atrial biopsies from 10 ToF and 10 ASD patients before (Pre-CPB) and after (Post-CPB) surgery. Pre-CPB samples showed significant differential expression of 72 genes (DEGs), 28 of which were overexpressed in ToF and 44 in ASD. According to Gene Ontology annotation, the mostly enriched biological processes were represented by matrix organization and cell adhesion in ToF and by muscle development and contractility in ASD specimens. GSEA highlighted the specific enrichment of known hypoxia gene sets in ToF samples, pointing to a role for hypoxia in disease pathogenesis. The post-CPB myocardium exhibited significant alterations in the expression profile of genes related to transcription regulation, growth/apoptosis, inflammation, cell adhesion/matrix organization, and oxidative stress. Among DEGs, only 70 were common to the two disease groups, whereas 110 and 24 were unique in ToF and ASD, respectively. Interestingly, gene expression changes in ASD samples followed a consensus hypoxia profile. These data define ToF- and ASD-specific myocardial transcriptional signatures and demonstrate differential gene reprogramming in response to CPB in the two pathologies, with potential prognostic and therapeutic implications.
2020-01-21 | GSE132176 | GEO
Project description:Macrobrachium nipponense is one of the commonest species threatened by ambient superfluous nitrite. The mechanism of nitrite stress at the molecular level was studied using de novo RNA-Seq to explore the molecular pathways in M. nipponense exposed to the acute nitrite stress (26.05 mg/L nitrite-N) for 24h and the chronic nitrite stress (6.58 mg/L nitrite-N) for 21d. A total of 175.13 million reads were obtained and assembled into 58,871 unigenes with an average length of 1,028.7 bp and N50 of 1,294bp. 2,824 and 2,610 unigenes in the acute and chronic nitrite stress were significantly differentially expressed respectively. Based on the change in GO analysis and KEGG pathway analysis, pathways both in the acute and chronic nitrite stress were glycosphingolipid biosynthesis - ganglio series, alanine aspartate and glutamate metabolism, biotin metabolism and amino sugar and nucleotide sugar metabolism which revealed the commonly functional pathways in acute and chronic nitrite stress. The markedly altered pathways were divided into four sections of immunity, metabolism, cell and others. Immunity section contained the most pathways among the classifications as phagosome, folate biosynthesis, glycerolipid metabolism, glycine, serine and threonine metabolism, selenoamino acid metabolism, cysteine and methionine metabolism, amino sugar and nucleotide sugar metabolism and taurine and hypotaurine metabolism in the acute nitrite stress and lysosome, alanine, aspartate and glutamate metabolism, arginine and proline metabolism, glycosaminoglycan degradation and amino sugar and nucleotide sugar metabolism in the chronic nitrite stress. This is the first report of whole molecular responses of M. nipponense under acute and chronic nitrite stress through de novo transcriptome sequencing. The findings of this study will further promote the understanding of the underlying molecular mechanisms of the nitrite stress for crustacean species.
2016-11-04 | GSE74684 | GEO
Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury.
2013-09-05 | GSE44925 | GEO