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PROVIDER: PRJNA846864 | ENA |
REPOSITORIES: ENA
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Project description:Macrophage dysfunction and polarization plays key role in chronic inflammation associated with diabetes and its complications. However, the effect of diabetes on macrophage transcriptome including long non-coding RNAs is not known. Here, we analyzed global changes in transcriptome of bone marrow macrophages isolated from type 2 diabetic db/db mice and control littermates db/+ mice using high throughput RNA-seq technique. Data analysis showed that expression of genes relevant to fibrosis, cell adhesion and inflammation were altered in diabetic db/db mice relative to control db/+ mice. Furthermore, expression of several known and novel long non coding RNAs and nearby genes was altered in db/db mice. Gene ontology and IPA showed activation of signaling netwroks relevant to fibrosis, cell adhesion and inflammatory pathways . This study for the first time demonstrated that diabetes profoundly affects macrophage transcriptome including expression of long non coding RNAs and altered the levels of genes relevant to diabetes complications. Bone marrow macrophages were isolated from 12 weeks old type 2 diabetic male db/db mice and control littermates db/+ mice. These were differentiated in culture for 7-8 days in the presence of 10 ng/ml of MCSF-1 (BMMC) or 20 ng/ml of GM-CSF (BMGM). Then RNA was extracted and used for RNA-seq.
2014-09-15 | E-GEOD-54154 | biostudies-arrayexpress
Project description:Macrophage dysfunction and polarization plays key role in chronic inflammation associated with diabetes and its complications. However, the effect of diabetes on macrophage transcriptome including long non-coding RNAs is not known. Here, we analyzed global changes in transcriptome of bone marrow macrophages isolated from type 2 diabetic db/db mice and control littermates db/+ mice using high throughput RNA-seq technique. Data analysis showed that expression of genes relevant to fibrosis, cell adhesion and inflammation were altered in diabetic db/db mice relative to control db/+ mice. Furthermore, expression of several known and novel long non coding RNAs and nearby genes was altered in db/db mice. Gene ontology and IPA showed activation of signaling netwroks relevant to fibrosis, cell adhesion and inflammatory pathways . This study for the first time demonstrated that diabetes profoundly affects macrophage transcriptome including expression of long non coding RNAs and altered the levels of genes relevant to diabetes complications.
2014-09-15 | GSE54154 | GEO
Project description:The pathogenesis of diabetic kidney disease (DKD) involves multifactorial processes that converge to initiate and advance the disease. Although DKD is not typically classified an inflammatory glomerular disease, mounting evidence supports the involvement of renal inflammation as a key contributor in DKD pathogenesis. However, detailed characteristics of specific immune cell types in the context of diabetic kidneys remain poorly understood. To capture the gene expression changes in specific immune cell subsets in early DKD, we performed a single-cell transcriptomic analysis of CD45-enriched kidney immune cells from control and diabetic OVE26 mice. Unsupervised clustering identified 11 distinct cell types that represented the major immune cells and an unidentified cell type. Further analysis of mononuclear phagocytes showed increased macrophage subsets in the diabetic kidneys and that pro-inflammatory and anti-inflammatory macrophages were concomitantly increased. Moreover, rather than in discrete M1 or M2 states, many macrophage subsets expressed genes consistent with the continuum of activation and differentiation states, and that their gene expression shifted toward increased inflammatory and differentiated status in the diabetic kidneys. Our study provides a comprehensive analysis of immune cell transcriptomic profiles in mouse DKD and underscores the dynamic macrophage activation in promoting DKD.
2022-11-08 | GSE195799 | GEO
Project description:Neutrophil extracellular traps (NETs) promote inflammation and atherosclerosis progression. In diabetes they are increased and impair wound healing, during which inflammation normally resolves. Atherosclerosis regression, a process resembling wound healing, is also impaired in diabetes. Thus, we hypothesized that NETs impede atherosclerosis regression in diabetes through unresolved inflammation. Objective: To investigate in diabetes the effect of NETs on plaque macrophage inflammation and whether NETs reduction improves atherosclerosis regression. Findings: Transcriptomic profiling of plaque macrophages from NET positive and negative areas in Ldlr-/- mice revealed inflammasome and glycolysis pathway upregulation, indicating a pro-inflammatory phenotype. During atherosclerosis regression in non-diabetic mice, plaque NET content decreased. In contrast, in diabetic mouse plaques NETs were enriched and persisted after lipid-lowering. DNase1 treatment (to degrade NETs) of diabetic mice reduced plaque NETs and macrophage inflammation and improved atherosclerosis regression after lipid-lowering. Conclusions: NETs decline during atherosclerosis regression in non-diabetic mice, but persist in diabetes and impair regression by exacerbating macrophage inflammation. DNase1 reduced diabetic plaque NETs and macrophage inflammation, and restored atherosclerosis resolution after lipid-lowering, despite ongoing hyperglycemia. Given that humans with diabetes also exhibit impaired atherosclerosis resolution with lipid-lowering, these data suggest that NETs contribute to the increased CVD risk in this population.
2020-05-12 | GSE145200 | GEO
Project description:Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease. Emerging evidence suggests that complement activation is involved in the pathogenesis of DN. The aim of this study was to investigate the pathogenic role of C3a and C3a receptor (C3aR) in DN. The expression of C3aR was examined in the renal specimen of DN patients. Using a C3aR gene knockout mice (C3aR-/-), we evaluated kidney injury in diabetic mice. The mouse gene expression microarray was performed to further explore the pathogenic role of C3aR. Then the underlying mechanism was investigated in vitro with macrophage treated with C3a. Compared with normal controls, the renal expression of C3aR was significantly increased in DN patients. C3aR-/- diabetic mice developed less severe diabetic renal damage compared with WT diabetic mice, exhibiting significantly lower level of albuminuria and milder renal pathological injury. Microarray profiling uncovered significantly suppressed inflammatory responses and T cell adaptive immunity in C3aR-/- diabetic mice compared with WT diabetic mice and this result was further verified by immunohistochemical staining of renal CD4+, CD8+ T cells and macrophages infiltration. In vitro study demonstrated C3a can enhance macrophages secreted cytokines which could induce inflammatory responses and differentiation of T cell lineage. In conclusion, C3aR deficiency could attenuate diabetic renal damage through suppressing inflammatory responses and T cell adaptive immunity, possibly by influencing macrophages secreted cytokines. Thus, C3aR may be a promising therapeutic target for DN.
2020-04-10 | GSE133597 | GEO
Project description:Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and end-stage renal disease. Emerging evidence suggests that complement activation is involved in the pathogenesis of DN. The aim of this study was to investigate the pathogenic role of C3a and C3a receptor (C3aR) in DN. The expression of C3aR was examined in the renal specimen of DN patients. Using a C3aR gene knockout mice (C3aR-/-), we evaluated kidney injury in diabetic mice. The mouse gene expression microarray was performed to further explore the pathogenic role of C3aR. Then the underlying mechanism was investigated in vitro with macrophage treated with C3a. Compared with normal controls, the renal expression of C3aR was significantly increased in DN patients. C3aR-/- diabetic mice developed less severe diabetic renal damage compared with WT diabetic mice, exhibiting significantly lower level of albuminuria and milder renal pathological injury. Microarray profiling uncovered significantly suppressed inflammatory responses and T cell adaptive immunity in C3aR-/- diabetic mice compared with WT diabetic mice and this result was further verified by immunohistochemical staining of renal CD4+, CD8+ T cells and macrophages infiltration. In vitro study demonstrated C3a can enhance macrophages secreted cytokines which could induce inflammatory responses and differentiation of T cell lineage. In conclusion, C3aR deficiency could attenuate diabetic renal damage through suppressing inflammatory responses and T cell adaptive immunity, possibly by influencing macrophages secreted cytokines. Thus, C3aR may be a promising therapeutic target for DN.
2020-04-10 | GSE133596 | GEO
Project description:Objective: Macrophages play key roles in inflammation and diabetic vascular complications. Emerging evidence implicates long noncoding RNAs (lncRNAs) in inflammation, but their role in macrophage dysfunction associated with inflammatory diabetic complications is unclear and was therefore investigated in this study. Approach and Results: RNA-sequencing and RT-qPCR demonstrated that a lncRNA Dynamin 3 opposite strand (Dnm3os) is upregulated in bone marrow derived macrophages from type2 diabetic (T2D) db/db mice, diet-induced insulin-resistant mice and diabetic ApoE-/- mice, as well as in monocytes from T2D patients relative to controls. Diabetic conditions (High glucose and palmitic acid) induced Dnm3os in mouse macrophages and THP1 human monocytes. Promoter reporter analysis and chromatin-immunoprecipitation (ChIP) assays demonstrated that diabetic conditions induce Dnm3os via NF-kB activation. RNA-FISH and RT-qPCRs of sub-cellular fractions demonstrated nuclear localization and chromatin enrichment of Dnm3os in macrophages. Stable overexpression of Dnm3os in macrophages altered global histone modifications and upregulated inflammation and immune response genes, and phagocytosis. Conversely, siRNA mediated knockdown of Dnm3os attenuated these responses. RNA pull-down assays with macrophage nuclear lysates identified nucleolin and ILF-2 as protein binding partners of Dnm3os, which was further confirmed by RNA-IP and RNA-FISH-immunofluorescence. Furthermore, nucleolin levels were decreased in diabetic conditions, and its knockdown enhanced Dnm3os-induced inflammatory gene expression and histone H3K9-acetylation at their promoters. Conclusions: These results demonstrate novel mechanisms involving upregulation of lncRNA Dnm3os, disruption of its interaction with nucleolin, and epigenetic modifications at target genes that promote macrophage inflammatory phenotype in diabetes. The data could lead to lncRNA-based therapies for inflammatory diabetes complications.
2018-08-23 | GSE107557 | GEO
Project description:Objective: To define the role of epigenetics, particularly DNA methylation in adaptive vascular growth in hyperlipidemic and type 2 diabetic mouse models of hind limb ischemia Methods: Unilateral hindlimb ischemia was induced by ligating femoral artery proximal to the bifurcation of superficial and deep femoral artery. DNA was isolated from ischemic muscles collected at day 7 after ischemia induction using DNeasy Tissue kit (Qiagen). 5 µg of genomic DNA was sheared into small fragments with a mean size of 150 bp by using a Covaris⢠S2 sonicator System. Quality of the fragmentation was analyzed with Bioanalyzer. Fragmented DNA samples were used for preparation of DNA fragment libraries and sequenced on the SOLiD4 sequencing instrument on one flow cell for 50 bp reads. The sequencing reads were mapped to mus musculus genome build mm9. Data was analyzed by using Bioscope. The samples were normalized with the MEDIPS package in R/B Bioconductor. The analysis of CpG methylation was done primarily in the proximal promoter regions encompassing a region of â1kb upstream of the transcription start site (TSS) and +500 bp downstream of the TSS. Comparisons were performed between hyperlipidemic versus controls and diabetic versus controls to detect differentially methylated regions. R package Limma was used for performing the statistical testing between the groups. Results: When visualizing the whole normalized data the samples did not cluster according to the sample groups. Especially two samples from hyperlipidemic and diabetic ischemic muscles differed clearly from the rest of the samples. To detect the differentially methylated genes, stringent thresholds for p-values and fold change values were chosen to list a reasonable number of genes. Upon filtering, significant differences in the methylation patterns of the sample groups were observed. More importantly, when clustering only the filtered genes, the samples clustered clearly according to the sample groups giving evidence of condition-dependent behavior. Using a threshold of methylation fold change of >1.2 and p value <0.05, we identified 397 and 446 genes to be hypomethylated in hyperlipidemic and diabetic ischemic muscles respectively compared to controls. There were 46 genes commonly shared, but still having a unique pattern of hypomethylation in 371 and 394 genes in hyperlipidemic and diabetic ischemic muscles respectively compared to controls. Similarly, there were 371 and 394 genes hypermethylated in hyperlipidemic and diabetic ischemic respectively compared to controls. Interestingly, we found 264 genes to be commonly hypermethylated, whereas 107 and 130 genes were uniquely hypermethylated in hyperlipidemic and diabetic ischemic muscles respectively. Thus, proximal promoter methylation suggested a shared, yet distinct pattern of DNA methylation in ischemic muscles of hyperlipidemic and type 2 diabetic mice compared to controls. Out of 397 genes that were hypomethylated in hyperlipidemic ischemic muscle, 68 genes were shown to be upregulated in âproinflammatory M1 macrophagesâ as shown by recent studies. Similarly, out of the 371 hypermethylated genes 93 genes were shown to be upregulated in âanti-inflammatory and proangiogenic M2 macrophagesâ as described recently. Out of 446 hypomethylated genes in diabetic ischemic muscle, 65 genes were shown to be upregulated in âproinflammatory M1 macrophagesâ as shown recently. Similarly, out of 394 hypermethylated genes 105 genes were specifically upregulated in âanti-inflammatory and proangiogenic M2 macrophagesâ as shown recently. qRT-PCR analysis suggested an inverse relationship between proximal promoter hypermethylation and mRNA expression in a subset of M2 macrophage specific genes in hyperlipidemic and type 2 diabetic ischemic muscles compared to control ischemic muscles. Conclusions: Our results suggest a role of epigenetics particularly proximal promoter DNA methylation in macrophage polarization and their contribution to angiogenesis and tissue repair in hyperlipidemic and type 2 diabetic mouse models of hind limb ischemia. Epigenetics at the level of DNA methylation may act as a deciding factor in promoting a pro or anti-inflammatory phenotype of macrophages critical in cardiovascular diseases. Ischemic skeletal muscle DNA methylation sequencing of triplicate samples from C57BL/6J (WT) mice, hyperlipidemic mice (LDLR-/-ApoB100/100 , C57BL/6J background) and type 2 diabetic mice (IGF-II/LDLR-/-ApoB100/100 , C57BL/6J background) using SoliD4 sequencing platform
2015-12-21 | E-GEOD-42092 | biostudies-arrayexpress
Project description:Renal gene expression in uninephrectomized diabetic OVE26 mice
| PRJNA126337 | ENA
Project description:Dysregulation of macrophage populations at the wound site is responsible for the non-healing state of chronic wounds. The molecular mechanisms underlying macrophage dysfunction and its control in diabetes are largely unexplored on an epigenetic level. Here, we report that acetyl histone-H3 (Lys27), an epigenetic mark regulating the macrophage transcriptome, is lost in the hostile tissue microenvironment in diabetes. The diabetic microenvironment, profoundly suppresses the acetylation of histone by activating HDACs-dependent deacetylation pathways. This, in consequence, suppress the STAT1 signaling in macrophages maintained in diabetic conditions. Interestingly, the HDAC inhibitor butyrate - via restoring the acetyl histone-H3 (Lys27)-dependent transcriptome - effectively rescues macrophage functions in a diabetic microenvironment. Butyrate reinstalls the STAT1 mediated transcription program and consequently macrophage activity depicting a unique fingerprint of tissue regeneration and inflammation control even in a hostile diabetic microenvironment. Most interesting, butyrate breaks the vicious cycle of inflammation in diabetic wounds. Our study offers novel pathogenic insight and the unique opportunity to reverse perturbed macrophage function thus holding promise to successfully treat diabetic and other chronic wounds and conditions of unrestrained inflammation.
2021-09-14 | GSE183965 | GEO