Long non-coding RNA Dlx6os1 serves as a potential treatment target for diabetic nephropathy via regulating multiple apoptosis and inflammation-related pathways derived from RNA-Seq
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE145301 | GEO | 2020/08/11
REPOSITORIES: GEO
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Project description:Validation of predicted gene expression of human mesangial cells after 24h Tacrolimus stimulus Objective: To evaluate tacrolimus as therapeutic option for diabetic nephropathy (DN) based on molecular profile and network-based molecular model comparisons. Materials and Methods: We generated molecular models representing pathophysiological mechanisms of DN and tacrolimus mechanism of action (MoA) based on literature derived data and transcriptomics datasets. Shared enriched molecular pathways were identified based on both model datasets. A newly generated transcriptomics dataset studying the effect of tacrolimus on mesangial cells in vitro was added to identify mechanisms in DN pathophysiology. We searched for features in interference between the DN molecular model and the tacrolimus MoA molecular model already holding annotation evidence as diagnostic or prognostic biomarker in the context of DN. Results: Thirty nine molecular features were shared between the DN molecular model, holding 252 molecular features and the tacrolimus MoA molecular model, holding 209 molecular features, with six additional molecular features affected by tacrolimus in mesangial cells. Significantly affected molecular pathways by both molecular model sets included cytokine-cytokine receptor interactions, adherens junctions, TGF-beta signaling, MAPK signaling, and calcium signaling. Molecular features involved in inflammation and immune response contributing to DN progression were significantly downregulated by tacrolimus (e.g. the tumor necrosis factor alpha (TNF), interleukin 4, or interleukin 10). On the other hand, pro-fibrotic stimuli being detrimental to renal function were induced by tacrolimus like the transforming growth factor beta 1 (TGFB1), endothelin 1 (EDN1), or type IV collagen alpha 1 (COL4A1). Conclusion: Patients with DN and elevated TNF levels might benefit from tacrolimus treatment regarding maintaining GFR and reducing inflammation. TGFB1 and EDN1 are proposed as monitoring markers to assess degree of renal damage. Next to this stratification approach, the use of drug combinations consisting of tacrolimus in addition to ACE inhibitors, angiotensin receptor blockers, TGFB1- or EDN1-receptor antagonists might warrant further studies. comparison of gene expression of human mesangial cells after 24h Tacrolimus vs. Ctrl; 4 independent experiments were conducted (4xTacrolimus 24h and 4x ctrl. 24h with Drug solvent (DMSO))
2016-08-01 | E-GEOD-84908 | biostudies-arrayexpress
Project description:Mesangial cells (MCs) in the kidney are central to maintaining glomerular integrity, and their impairment leads to major glomerular diseases including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying molecular mechanism is poorly understood. Here, we show that YAP and TAZ, the final effectors of the Hippo pathway, are highly increased in MCs of patients with DN and of Zucker diabetic fatty rats. Moreover, high glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse model MCs recapitulates the hallmarks of DN, including excessive proliferation of MCs and extracellular matrix deposition, endothelial cell impairment, glomerular sclerosis, albuminuria, and reduced glomerular filtration rate. Mechanistically, activated YAP/TAZ bind and stabilize N-Myc protein, one of the Myc family of oncogenes. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and eventually to MC impairments and DN pathogenesis. Together, these findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.
2022-02-01 | GSE195751 | GEO
Project description:Validation of predicted gene expression of human mesangial cells after 24h Tacrolimus stimulus Objective: To evaluate tacrolimus as therapeutic option for diabetic nephropathy (DN) based on molecular profile and network-based molecular model comparisons. Materials and Methods: We generated molecular models representing pathophysiological mechanisms of DN and tacrolimus mechanism of action (MoA) based on literature derived data and transcriptomics datasets. Shared enriched molecular pathways were identified based on both model datasets. A newly generated transcriptomics dataset studying the effect of tacrolimus on mesangial cells in vitro was added to identify mechanisms in DN pathophysiology. We searched for features in interference between the DN molecular model and the tacrolimus MoA molecular model already holding annotation evidence as diagnostic or prognostic biomarker in the context of DN. Results: Thirty nine molecular features were shared between the DN molecular model, holding 252 molecular features and the tacrolimus MoA molecular model, holding 209 molecular features, with six additional molecular features affected by tacrolimus in mesangial cells. Significantly affected molecular pathways by both molecular model sets included cytokine-cytokine receptor interactions, adherens junctions, TGF-beta signaling, MAPK signaling, and calcium signaling. Molecular features involved in inflammation and immune response contributing to DN progression were significantly downregulated by tacrolimus (e.g. the tumor necrosis factor alpha (TNF), interleukin 4, or interleukin 10). On the other hand, pro-fibrotic stimuli being detrimental to renal function were induced by tacrolimus like the transforming growth factor beta 1 (TGFB1), endothelin 1 (EDN1), or type IV collagen alpha 1 (COL4A1). Conclusion: Patients with DN and elevated TNF levels might benefit from tacrolimus treatment regarding maintaining GFR and reducing inflammation. TGFB1 and EDN1 are proposed as monitoring markers to assess degree of renal damage. Next to this stratification approach, the use of drug combinations consisting of tacrolimus in addition to ACE inhibitors, angiotensin receptor blockers, TGFB1- or EDN1-receptor antagonists might warrant further studies.
2016-08-01 | GSE84908 | GEO
Project description:To gain a comprehensive understanding of emetine's impact on high glucose-induced M1 macrophage polarization in the pathogenesis of diabetic nephropathy (DN), we employed transcriptome sequencing. Our study included two experimental groups: the high glucose-induced damage group and the high glucose-induced damage with emetine pretreatment group. Differential gene expression analysis, accompanied by functional enrichment analysis, was conducted to identify crucial pathways and biological processes involved. This investigation provides significant insights into the role of emetine in DN, enhancing our knowledge regarding its underlying mechanisms. Furthermore, this research contributes to a deeper comprehension of the pathogenesis of diabetic nephropathy and offers valuable prospects for the development of potential therapeutic targets and strategies for diabetic nephropathy.
2024-01-02 | GSE239385 | GEO
Project description:Current diagnostic methods for diabetic nephropathy (DN) lack precision, especially in early stages and monitoring progression. This study aims to find potential biomarkers for DN progression and evaluate their accuracy. Using serum samples from healthy controls (NC), diabetic patients (DM), early-medium stage DN (DN-EM), and late-stage DN (DN-L), researchers employed quantitative proteomics and Mfuzz clustering analysis revealed 15 proteins showing increased expression during DN progression, hinting at their biomarker potential. Combining Mfuzz clustering with weighted gene co-expression network analysis (WGCNA) highlighted five candidates (HMGB1, CD44, FBLN1, PTPRG, and ADAMTSL4). HMGB1 emerged as a promising biomarker, closely correlated with renal function changes. Experimental validation supported HMGB1’s upregulation under high glucose conditions, reinforcing its potential as an early detection biomarker for DN. This research advances DN understanding and identifies five potential biomarkers, notably HMGB1, as a promising early monitoring target. These findings set the stage for future clinical diagnostic applications in DN.
2023-12-28 | PXD047872 | Pride
Project description:Background The mechanism by which LMWH can delay the progression of diabetic nephropathy (DN) is not fully understood. Methods To further reveal the mechanism of LMWH treatment DN progression, we first verified the effect of LMWH in treatment DN through mouse models, and then quantified the kidney proteome by label-free, combined with bioinformation analysis to find key differentially expressed proteins. The mechanism by which LMWH causes differences in protein expression is revealed by cell experiments. Results Compared with the diabetic nephropathy group, the downstream proteins FABP1, Acaa1b, Acox2, Hmgcs2 and PLTP of the PPAR signaling pathway were significantly upregulated in the LMWH treatment group. The HS-binding protein FABP1 was used as the key protein to study the cellular mechanism, and it was found that the high glucose-high fat environment would degrade the HS of renal tubular epithelial cells, thereby reducing the endocytosis recruitment effect of renal tubules on FABP1. Conclusions LMWH can protect the HS of DN tubular epithelial cells from being destroyed, thereby ensuring the normal endocytosis of HS-mediated FABP1, reducing the loss of FABP1, and promoting the PPAR pathway to delay the progression of DN.
2024-10-17 | PXD045022 | Pride
Project description:Transcriptome comparison of glomeruli from kidneys with diabetic nephropathy (DN) and glomeruli from the unaffected portion of tumor nephrectomies. Transcritomics profile of glomeruli in DN patients explored SRGAP2 was strongly associated with proteinuria and involved in podocyte cytoskeleton organization
2018-07-31 | GSE96804 | GEO
Project description:Idiopathic nodular mesangial sclerosis, also called idiopathic nodular glomerulosclerosis (ING) is a rare clinical entity with unclear pathogenesis. The hallmark of this disease is the presence of nodular mesangial sclerosis on histology without clinical evidence of diabetes mellitus or other predisposing diagnoses. To achieve insights into its pathogenesis, we queried the clinical, histopathologic and transcriptomic features of ING and nodular diabetic nephropathy (DN)
2020-12-09 | GSE162830 | GEO
Project description:The early diagnosis of diabetic nephropathy (DN) is essential to improve the prognosis and manage patients affected by this disease. Standard biomarkers, including albuminuria and glomerular filtration rate, are limited to give a precise result. New molecular biomarkers are needed to identify better and predict DN disease evolution. Characteristic DN biomarkers can be identified using transcriptomic analysis. Blood samples were used to isolate RNA for microarray expression using Agilent SurePrint G3 Human Gene Expression 8x60K v2 Microarrays, we evaluated the transcriptomic profile of controls , prediabetes, type-2 diabetes mellitus, and DN.
2022-09-16 | E-MTAB-12135 | biostudies-arrayexpress
Project description:The aim of this study is to compare renal transcriptome profiling between diabetic nephropathy (DN) and DN treated with human placenta-derived mesenchymal stem cells (PMSCs) groups. Twelve renal cortex samples (n=6 for each DN and treatment group) were sequenced using Illumina Hiseq 4000. We identified 90 differentially expressed genes between DN and treatment griups with |og2 FoldChange| ≥1 and p value <0.05. Our study represents the first detailed analysis of renal transcriptomes, with biologic replicates, generated by RNA-seq technology.
2020-06-26 | GSE153217 | GEO