Oxidative Stress in the Pathophysiology of Kidney Disease: Implications for Noninvasive Monitoring and Identification of Biomarkers.
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ABSTRACT:
SUBMITTER: Gyuraszova M
PROVIDER: S-EPMC7007944 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDiabetic kidney disease (DKD) is a leading cause of end-stage renal disease throughout the world. In kidney disease, oxidative stress has been linked to both antioxidant depletions and increased reactive oxygen species (ROS) production. Thus, the objective of this study was to identify biomarkers related to oxidative stress in DKD.MethodsThe gene expression profile of the DKD was extracted from the Gene Expression Omnibus (GEO) database. The identification of the differentially expressed genes (DEGs) was performed using the "limma" R package, and weighted gene coexpression network analysis (WGCNA) was used to find the gene modules that were most related to DKD. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed using "Org.Hs.eg.db" R package. The protein-protein interaction (PPI) network was constructed using the STRING database. The hub genes were identified by the Molecular Complex Detection (MCODE) plug-in of Cytoscape software. The diagnostic capacity of hub genes was verified using the receiver operating characteristic (ROC) curve. Correlations between diagnostic genes were analyzed using the "corrplot" package. In addition, the miRNA gene transcription factor (TF) network was used to explain the regulatory mechanism of hub genes in DKD.ResultsDEGs analysis and WGCNA-identified 160 key genes were identified in DKD patients. Among them, nine oxidative stress-related genes were identified as candidate hub genes for DKD. Using the PPI network, five hub genes, NR4A2, DUSP1, FOS, JUN, and PTGS2, were subsequently identified. All the hub genes were downregulated in DKD and had a high diagnostic value of DKD. The regulatory mechanism of hub genes was analyzed from the miRNA gene-TF network.ConclusionOur study identified NR4A2, DUSP1, FOS, JUN, and PTGS2 as hub genes of DKD. These genes may serve as potential therapeutic targets for DKD patients.
| S-EPMC9825216 | biostudies-literature
Project description:ObjectivesThe goal of this study was to validate a pathway-specific reporter gene that could be used to noninvasively image the oxidative status of progenitor cells.BackgroundIn cell therapy studies, reporter gene imaging plays a valuable role in the assessment of cell fate in living subjects. After myocardial injury, noxious stimuli in the host tissue confer oxidative stress to transplanted cells that may influence their survival and reparative function.MethodsRat mesenchymal stromal cells (MSCs) were studied for phenotypic evidence of increased oxidative stress under in vitro stress. On the basis of their up-regulation of the pro-oxidant enzyme p67(phox) subunit of nicotinamide adenine dinucleotide phosphate (NAD[P]H oxidase p67(phox)), an oxidative stress sensor was constructed, comprising the firefly luciferase (Fluc) reporter gene driven by the NAD(P)H p67(phox) promoter. MSCs cotransfected with NAD(P)H p67(phox)-Fluc and a cell viability reporter gene (cytomegalovirus-Renilla luciferase) were studied under in vitro and in vivo pro-oxidant conditions.ResultsAfter in vitro validation of the sensor during low-serum culture, transfected MSCs were transplanted into a rat model of myocardial ischemia/reperfusion (IR) and monitored by using bioluminescence imaging. Compared with sham controls (no IR), cardiac Fluc intensity was significantly higher in IR rats (3.5-fold at 6 h, 2.6-fold at 24 h, 5.4-fold at 48 h; p < 0.01), indicating increased cellular oxidative stress. This finding was corroborated by ex vivo luminometry after correcting for Renilla luciferase activity as a measure of viable MSC number (Fluc:Renilla luciferase ratio 0.011 ± 0.003 for sham vs. 0.026 ± 0.004 for IR at 48 h; p < 0.05). Furthermore, in IR animals that received MSCs preconditioned with an antioxidant agent (tempol), Fluc signal was strongly attenuated, substantiating the specificity of the oxidative stress sensor.ConclusionsPathway-specific reporter gene imaging allows assessment of changes in the oxidative status of MSCs after delivery to ischemic myocardium, providing a template to monitor key biological interactions between transplanted cells and their host environment in living subjects.
| S-EPMC3710523 | biostudies-literature
Project description:IntroductionThe incidence of chronic kidney disease (CKD) has been increasing in recent years, gradually becoming a global health crisis. Due to limited treatment options, novel molecular pathways are urgently required to advance the treatment and diagnosis of CKD.Materials and methodsThe characteristics of differentially expressed genes (DEGs) in CKD patients were analyzed using Gene Expression Omnibus (GEO) database, and genes related to oxidative stress were retrieved from the Genecard database. Subsequently, a comprehensive approach was applied, including immune infiltration analysis, weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis, to identify hub genes among differentially expressed immune-related oxidative stress genes (DEIOSGs). Validation of hub genes was performed using an external data set, and diagnostic potential capability was evaluated through receiver operating curve (ROC) analysis. In animal experiments, the expression of hub genes in CKD was confirmed by inducing a CKD model through a 5/6 nephrectomy procedure. Finally, the relationship between these hub genes and clinical characteristics were assessed using the Nephroseq v5 database.Results29 DEIOSGs were identified by comprehensive bioinformatics analysis. PPI analysis screened the hub genes NCF2, S100A9, and SELL. ROC analysis demonstrated excellent diagnostic efficacy. Further validation from other databases and animal experiments confirmed a substantial upregulation in the expression of hub genes in CKD. Additionally, clinical correlation analysis established a clear link between hub gene expression and renal function deterioration.ConclusionsOur study confirms NCF2, S100A9, and SELL as diagnostic biomarkers associated with immune response and oxidative stress in CKD, suggesting their potential as novel targets for CKD diagnosis and treatment.
| S-EPMC10955299 | biostudies-literature
Project description:Cardiovascular diseases remain the most frequent cause of morbidity and mortality in patients with chronic kidney disease (CKD). The aim of the study was to assess the association between oxidative stress biomarkers and cardiovascular risk factors and left ventricular hypertrophy in children with CKD. Material and Methods. The studied group consisted of 65 patients aged 1.4-18.6 (mean 11.2) years with stages 1 to 5 CKD. Serum oxidized low-density lipoprotein (oxLDL), protein carbonyl group, creatinine, cystatin C, albumin, lipids, high-sensitivity C-reactive protein, intercellular adhesion molecule-1, insulin, plasma renin activity, and aldosterone levels were measured. Patients were divided into groups depending on CKD stage. Anthropometric measurements, ambulatory blood pressure (BP) measurements, and echocardiography with left ventricular mass (LVM) calculation were performed. Results. Serum oxLDL strongly correlated with creatinine (R = 0.246; p = 0.048), cystatin C (R = 0.346; p = 0.006), total cholesterol (R = 0.500; p < 0.001), triglycerides (R = 0.524; p < 0.001), low-density lipoprotein concentrations (R = 0.456; p < 0.001), and 24 hour BP values of systolic (R = 0.492; p = 0.002), diastolic (R = 0.515; p < 0.001), and mean arterial pressure (R = 0.537; p < 0.001). A significant correlation between oxLDL levels and LVM z-scores (R = 0.299; p = 0.016) was found. Conclusions. Hypertension and dyslipidemia correlated with lipid oxidation in children with CKD. oxLDLs seem to be valuable markers of oxidative stress in CKD patients, correlating with left ventricular hypertrophy.
| S-EPMC4739446 | biostudies-literature
Project description:Chronic Kidney Disease (CKD) is a cardinal feature of methylmalonic acidemia (MMA), a prototypic organic acidemia. Impaired growth, low activity, and protein restriction affect muscle mass and lower serum creatinine, which can delay diagnosis and management of renal disease. We have designed an alternative strategy for monitoring renal function based on administration of a pH sensitive MRI agent and assessed this in a mouse model. This protocol produced three metrics: kidney contrast, ~4% for severe renal disease mice compared to ~13% and ~25% for moderate renal disease and healthy controls, filtration fraction (FF), ~15% for severe renal disease mice compared to ~79% and 100% for moderate renal disease and healthy controls, and variation in pH, ~0.45 units for severe disease mice compared to 0.06 and 0.01 for moderate disease and healthy controls. Our results demonstrate that MRI can be used for early detection and monitoring of CKD.
| S-EPMC6693904 | biostudies-literature
Project description:Accumulating evidence indicates that oxidative stress plays a role in the pathophysiology of chronic kidney disease (CKD) and its progression; during renal replacement therapy, oxidative stress-derived oxidative damage also contributes to the development of CKD systemic complications, such as cardiovascular disease, hypertension, atherosclerosis, inflammation, anaemia, and impaired host defence. The main mechanism underlying these events is the retention of uremic toxins, which act as a substrate for oxidative processes and elicit the activation of inflammatory pathways targeting endothelial and immune cells. Due to the growing worldwide spread of CKD, there is an overwhelming need to find oxidative damage biomarkers that are easy to measure in biological fluids of subjects with CKD and patients undergoing renal replacement therapy (haemodialysis, peritoneal dialysis, and kidney transplantation), in order to overcome limitations of invasive monitoring of CKD progression. Several studies investigated biomarkers of protein oxidative damage in CKD, including plasma protein carbonyls (PCO), the most frequently used biomarker of protein damage. This review provides an up-to-date overview on advances concerning the correlation between plasma protein carbonylation in CKD progression (from stage 1 to stage 5) and the possibility that haemodialysis, peritoneal dialysis, and kidney transplantation improve plasma PCO levels. Despite the fact that the role of plasma PCO in CKD is often underestimated in clinical practice, emerging evidence highlights that plasma PCO can serve as good biomarkers of oxidative stress in CKD and substitutive therapies. Whether plasma PCO levels merely serve as biomarkers of CKD-related oxidative stress or whether they are associated with the pathogenesis of CKD complications deserves further evaluation.
| S-EPMC7707964 | biostudies-literature
Project description:Alzheimer's disease (AD), the most common form of dementia, has increasing incidence, increasing mortality rates, and poses a huge burden on healthcare. None of the currently approved drugs for the treatment of AD influence disease progression. Many clinical trials aiming at inhibiting amyloid plaque formation, increasing amyloid beta clearance, or inhibiting neurofibrillary tangle pathology yielded inconclusive results or failed. Meanwhile, research has identified many interlinked vicious cascades implicating oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, and has pointed to novel therapeutic targets such as improving mitochondrial bioenergetics and quality control, diminishing oxidative stress, or modulating the neuroinflammatory pathways. Many novel molecules tested in vitro or in animal models have proven efficient, but their translation into clinic needs further research regarding appropriate doses, delivery routes, and possible side effects. Cell-based therapies and extracellular vesicle-mediated delivery of messenger RNAs and microRNAs seem also promising strategies allowing to target specific signaling pathways, but need further research regarding the most appropriate harvesting and culture methods as well as control of the possible tumorigenic side effects. The rapidly developing area of nanotechnology could improve drug delivery and also be used in early diagnosis.
| S-EPMC9686795 | biostudies-literature
Project description:Intrarenal oxidative stress plays a critical role in the initiation and progression of diabetic kidney disease (DKD). Enhanced oxidative stress results from overproduction of reactive oxygen species (ROS) in the context of concomitant, insufficient antioxidant pathways. Renal ROS production in diabetes is predominantly mediated by various NADPH oxidases (NOXs), but a defective antioxidant system as well as mitochondrial dysfunction may also contribute. Recent Advances: Effective agents targeting the source of ROS generation hold the promise to rescue the kidney from oxidative damage and prevent subsequent progression of DKD. Critical Issues and Future Directions: In the present review, we summarize and critically analyze molecular and cellular mechanisms that have been demonstrated to be involved in NOX-induced renal injury in diabetes, with particular focus on the role of increased glomerular injury, the development of albuminuria, and tubulointerstitial fibrosis, as well as mitochondrial dysfunction. Furthermore, novel agents targeting NOX isoforms are discussed. Antioxid. Redox Signal. 25, 657-684.
| S-EPMC5069735 | biostudies-literature
Project description:Atherosclerosis is related to fat accumulation in the arterial walls and vascular stiffening, and results in acute coronary syndrome which is commonly associated with acute myocardial infarction. Oxidative stress participates in the pathogenesis of atherosclerosis. Thus, the inclusion of food sources of dietary antioxidants, such as different kinds of nuts, may improve biomarkers related to oxidative stress, contributing to a possible reduction in atherosclerosis progression. This article has briefly highlighted the interaction between oxidative stress, atherosclerosis, and cardiovascular disease, in addition to the effect of the consumption of different nuts and related dietary antioxidants-like polyphenols and vitamin E-on biomarkers of oxidative stress in primary and secondary cardiovascular prevention. Studies in vitro suggest that nuts may exert antioxidant effects by DNA repair mechanisms, lipid peroxidation prevention, modulation of the signaling pathways, and inhibition of the MAPK pathways through the suppression of NF-κB and activation of the Nrf2 pathways. Studies conducted in animal models showed the ability of dietary nuts in improving biomarkers of oxidative stress, such as oxLDL and GPx. However, clinical trials in humans have not been conclusive, especially with regards to the secondary prevention of cardiovascular disease.
| S-EPMC7146201 | biostudies-literature
Project description:BackgroundChronic kidney disease (CKD) has few objective symptoms, and it is difficult to make an early diagnosis by using existing methods. Therefore, new biomarkers enabling diagnosis of renal dysfunction at an early stage need to be developed. Here, we searched for new biomarkers of CKD by focusing on kidney-derived proteins that could sensitively reflect that organ's disease state.MethodsTo identify candidate marker proteins, we performed a proteomics analysis on renal influx and efflux blood collected from the same individual.ResultsProteomics analysis revealed 662 proteins in influx blood and 809 in efflux. From these identified proteins, we selected complement C1q as a candidate; the plasma C1q level was significantly elevated in the renal efflux of donors. Moreover, the plasma concentration of C1q in a mouse model of diabetic nephropathy was significantly increased, in association with increases in blood glucose concentration and urinary protein content. Importantly, we demonstrated that the tendency of C1q to increase in the plasma of CKD patients was correlated with a decrease in their estimated glomerular filtration rate.ConclusionOverall, our results indicate that our approach of focusing on kidney-derived proteins is useful for identifying new CKD biomarkers and that C1q has potential as a biomarker of renal function.
| S-EPMC8903635 | biostudies-literature