Effect of two weeks erythropoietin treatment on monocyte transcriptomes of cardiorenal patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE17582 | GEO | 2009/08/11
SECONDARY ACCESSION(S): PRJNA118687
REPOSITORIES: GEO
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Project description:Patients with combined heart and renal failure, also termed the cardiorenal syndrome (CRS), have high cardiovascular morbidity and mortality. Several key connectors between heart and kidney have been recognized, such as oxidative stress, inflammation, the renin-angiotensin system and the sympathetic nervous system. Monocytes are key players in the development of atherosclerosis and may act as a biosensor to detect changes in the systemic environment. Anemia, which occurs frequently in CRS, is partly due to an absolute and/or relative erythropoietin (EPO) deficiency. Until now, EPO treatment has largely been used to treat (renal) anemia, but recent research also showed beneficial non-hematopoietic effects such as anti-inflammatory and anti-oxidative capacities. The hypothesis of the present study was that monocyte gene expression profiles of cardiorenal patients compared to healthy controls reflect the systemic nature of CRS and are responsive to short-term treatment with Epo. The first aim was to investigate whether this short term treatment revealed non-hematopoietic EPO effects. The second aim was to address whether EPO dampens expression of genes involved in inflammation and oxidative stress. Given the variable response to EPO, the third aim was to test whether baseline gene expression profiles or the acute gene expression modulation by EPO are associated with EPO resistance. This study was part of a larger clinical trial in which hematopoietic and non-hematopoietic effects of EPO treatment for short and long term are assessed in CRS patients. Therefore, patients were randomized into 3 groups: (1) EPO, patients are kept on baseline low hemoglobin levels by phlebotomy for 6 months; (2) EPO, patients may rise in hemoglobin levels to defined maximum for 6 months; (3) No EPO. This gene expression analysis is focussed on EPO's short-term (2wk) effects in a subset of included patients. Group (1) and (2) were grouped for analysis, since both groups received EPO and no phlebotomy had been performed in the first 2 weeks. Monocytes were positively isolated from peripheral whole blood with CD14+ immunomagnetic beads. Total RNA was isolated and prepared for genome wide analyses using Illumina HumanRef8 V3.0 Beadchips. In total, 48 arrays were analyzed including 12 healthy controls, 18 CRS patients at baseline and 2 weeks after study enrollment. Twelve out of 18 patients received EPO during the two weeks. The supplementary file 'GSE17582_non-normalized_data.txt' contains non-normalized data for Samples GSM438053-GSM438100.
2009-08-11 | E-GEOD-17582 | biostudies-arrayexpress
Project description:Acute cardiorenal syndrome (CRS-1) is a morbid complication of acute cardiovascular disease. Mechanistic investigations have focused on intrarenal cellular signaling induced by ischemia/reperfusion. Additional signals, “cardiorenal connectors”, have been postulated, but investigation in CRS-1 has been limited by a paucity of animal models and technical limitations precluding discovery studies of glomerular filtrate. To address these limitations we developed a translational model of CRS-1, cardiac arrest and cardiopulmonary resuscitation (CA/CPR) and now report findings from a nanoscale mass spectrometry assay allowing proteomic exploration of Bowman’s space aspirate 2h after CA/CPR or sham procedure. Imaging, molecular weight and charge distribution, and minimal contribution of proteins from surrounding cell types confirmed the acquisition of filtrate. We detected filtration of low-molecular weight proteins specific to the heart following CA/CPR. Additional mass spectrometry performed on 24h urine collections from mice with deficient tubular endocytosis confirmed CA/CPR-specific cardiac protein filtration, and identified a novel, CA/CPR-specific, filtrate component: Cardiac LIM protein. Cardiac arrest-induced plasma release of Cardiac LIM protein occurred in mice and in critically-ill human cardiac arrest survivors and administration of recombinant cardiac LIM protein to mice altered renal function. Our findings demonstrate that glomerular filtrate is accessible to nanoscale proteomics and elucidate the population of proteins filtered 2h after acute cardiovascular crisis. The presence and identification of cardiac-specific proteins in renal filtrate suggest a potential novel signaling mechanism in CRS-1. We expect these findings to advance understanding of cardiorenal syndrome.
2019-02-27 | PXD012148 | Pride
Project description:Acute cardiorenal syndrome (CRS-1) is a morbid complication of acute cardiovascular disease. Mechanistic investigations have focused on intrarenal cellular signaling induced by ischemia/reperfusion. Additional cardiorenal connector signals have been postulated, but investigation in CRS-1 has been limited by a paucity of animal models and technical limitations precluding discovery studies of glomerular filtrate. To address these limitations, we developed a translational model of CRS-1, cardiac arrest and cardiopulmonary resuscitation (CA/CPR) in mice. Quantitative proteomics using isobaric tagging (10-plex TMT reagents, Thermo Fisher) was performed on 24h urine collections from mice with deficient tubular endocytosis and from littermate controls, before and after CA/CPR. Data acquisition used the SPS MS3 method on a Thermo Fusion Tribrid mass spectrometer for accurate reporter ion signals. The findings confirmed CA/CPR-specific cardiac proteins in urine and identified a novel CA/CPR-specific filtrate component: Cardiac LIM protein (CSRP3).
2019-02-27 | PXD012193 | Pride
Project description:Cardiorenal syndrome (CRS) type 4 is prevalent among the chronic kidney disease (CKD) population, with many patients dying from cardiovascular complications. However, limited data regarding cardiac transcriptional changes induced early by CKD is available. We used a murine unilateral ureteral obstruction (UUO) model to evaluate cardiac transcriptional regulation at 21 days post-surgery through RNA-seq and bioinformatics. UUO leads to significant kidney injury, low uremia, and pathological cardiac remodeling. RNA-seq analysis identified 76 differentially expressed genes (DEGs) in UUO hearts. Upregulated DEGs were significantly enriched in cell cycle and cell division pathways, immune responses, cardiac repair, inflammation, proliferation, oxidative stress, and apoptosis. Gene Set Enrichment Analysis further revealed mitochondrial oxidative bioenergetic pathways, autophagy, and peroxisomal pathways are downregulated in UUO hearts. Vimentin was also identified as an UUO-upregulated transcript. Our results emphasize the relevance of extensive transcriptional and epigenetic changes, mitochondrial dysfunction, homeostasis deregulation, fatty-acid metabolism alterations, and vimentin upregulation in CRS type 4 development.
2024-03-22 | GSE235751 | GEO
Project description:Erythropoietin (EPO) drives erythropoiesis and is secreted mainly by the kidney upon hypoxic or anemic stress. The paucity of EPO production in renal EPO-producing cells (REPs) causes renal anemia, one of the most common complications of chronic nephropathies. Although mitochondrial dysfunction is commonly observed in several renal and hematopoietic disorders, the mechanism by which mitochondrial quality control impacts renal anemia remains elusive. In this study, we showed that FUNDC1, a mitophagy receptor, plays a critical role in EPO-driven erythropoiesis induced by stresses. Mechanistically, EPO production is impaired in REPs in Fundc1-/- mice upon stresses, and the impairment is caused by the accumulation of damaged mitochondria, which consequently leads to the elevation of the reactive oxygen species (ROS) level and triggers inflammatory responses by up-regulating proinflammatory cytokines. These inflammatory factors promote the myofibroblastic transformation of REPs, resulting in the reduction of EPO production. We therefore provide a link between aberrant mitophagy and deficient EPO generation in renal anemia. Our results also suggest that the mitochondrial quality control safeguards REPs under stresses, which may serve as a potential therapeutic strategy for the treatment of renal anemia.
2021-05-07 | GSE158361 | GEO
Project description:Background and objectives: This report describes an unusual presentation of severe hypertension (HTN) in a subset of pediatric kidney recipients treated with a steroid avoidance pediatric renal transplantation protocol. The HTN was secondary to atypical, reno-vascular abnormalities (RVA) of the transplanted vasculature, temporally associated with erythropoietin (EPO) use. Design, setting, participants, and measurements: To investigate the clinical significance underlying this event, a retrospective clinical study of 100 pediatric renal transplants was undertaken (50 steroid-free and 50 matched steroid-based controls), with peripheral blood transcriptional analysis of four RVA patients and controls. Results: Regardless of a higher observed incidence of anemia (p < 0.001) and greater overall EPO usage in the first post-transplant year in steroid-free patients, the incidence of new-onset HTN at one yr was significantly less in the steroid-free cohort (p = 0.03). Nevertheless, early EPO (first week post-transplant) was significantly associated with the combinatory findings of new-onset HTN (p = 0.03) and RVA (p = 0.007). Molecular mechanisms of RVA injury were investigated further by peripheral blood cDNA microarray gene expression profiling. A panel of 42 transcripts differentiated patients with RVA and HTN from three sets of matched controls, with and without HTN and EPO use, with 100% concordance (p < 0.001). The biological processes governed by these significant genes suggest a role for EPO regulation of growth factor receptor ubiquitination as a putative mechanism for renal vascular injury. Conclusion: This study cautions against the use early post-transplant use of EPO in immunosuppression regimens with steroid minimization/avoidance, which may have an increased incidence of post-transplant anemia. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Disease State: patient with high blood pressure Keywords: Logical Set Using regression correlation
2008-10-21 | E-GEOD-13198 | biostudies-arrayexpress
Project description:Activation of hypoxia-inducible transcription factors (HIF) leading to expression of hundred of target genes is a fundamental mechanism in acute and chronic kidney disease mediating protective but also possibly harmful effects. Furthermore, dysregulation of the HIF pathway in chronic kidney disease causes renal anemia through insufficient induction of erythropoietin (EPO) in interstitial cells. Hence, pharmacological compounds to treat renal anemia by stabilizing HIF have recently been introduced to the clinical practice. RNA-seq analysis was performed in primary renal tubular cells to analyse the effect of HIF stabilization on the expression of pathogenic Mucin1 (MUC1) variants. This study links the regulation of the kidney-disease gene MUC1 with the HIF-pathway in renal tubular cells.
2023-06-07 | GSE224177 | GEO
Project description:Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production have not yet been resolved, limiting effective cell-based therapies for anemia. Here, we performed single-cell profiling of an Epo reporter mouse to molecularly identify Epo-producing cells under hypoxic conditions. We report that a distinct and homogeneous population of kidney stromal cells, which we name Norn cells, are the sole source of Epo production in vivo. Extensive characterization of the Norn epigenetic and transcriptional landscapes revealed Norn-specific markers, pathways, and transcription factor circuits conserved from mice to humans. These findings open new avenues to functionally dissect EPO gene regulation in human evolution and disease, and pave the way for the next generation of genetic and cell-based approaches for EPO therapies.
2023-03-13 | GSE193321 | GEO
Project description:Background and objectives: This report describes an unusual presentation of severe hypertension (HTN) in a subset of pediatric kidney recipients treated with a steroid avoidance pediatric renal transplantation protocol. The HTN was secondary to atypical, reno-vascular abnormalities (RVA) of the transplanted vasculature, temporally associated with erythropoietin (EPO) use. Design, setting, participants, and measurements: To investigate the clinical significance underlying this event, a retrospective clinical study of 100 pediatric renal transplants was undertaken (50 steroid-free and 50 matched steroid-based controls), with peripheral blood transcriptional analysis of four RVA patients and controls. Results: Regardless of a higher observed incidence of anemia (p < 0.001) and greater overall EPO usage in the first post-transplant year in steroid-free patients, the incidence of new-onset HTN at one yr was significantly less in the steroid-free cohort (p = 0.03). Nevertheless, early EPO (first week post-transplant) was significantly associated with the combinatory findings of new-onset HTN (p = 0.03) and RVA (p = 0.007). Molecular mechanisms of RVA injury were investigated further by peripheral blood cDNA microarray gene expression profiling. A panel of 42 transcripts differentiated patients with RVA and HTN from three sets of matched controls, with and without HTN and EPO use, with 100% concordance (p < 0.001). The biological processes governed by these significant genes suggest a role for EPO regulation of growth factor receptor ubiquitination as a putative mechanism for renal vascular injury. Conclusion: This study cautions against the use early post-transplant use of EPO in immunosuppression regimens with steroid minimization/avoidance, which may have an increased incidence of post-transplant anemia. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Disease State: patient with high blood pressure Keywords: Logical Set
2008-10-21 | GSE13198 | GEO
Project description:Receptor-mediated mitophagy regulates EPO production and protects against renal anemia
| PRJNA664995 | ENA