LRG1 loss effectively restrains glomerular TGF-β signaling to attenuate DKD in diabetic mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1122216 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:scRNA-seq analysis confirmed that increased LRG1 is limited to GECs in early diabetic kidneys. As anticipated, LRG1 loss significantly attenuated diabetic glomerulopathy including podocyte loss, and improved renal function. scRNA-seq analysis demonstrated that LRG1 loss was sufficient to reverse all significant molecular pathway changes in diabetic mouse GECs, which were also associated with the dampening of TGF-β-induced gene expression. Moreover, LRG1 loss also led to a significant attenuation of TGF-β-mediated gene expression in podocytes and mesangial cells of diabetic mice. These results indicate that increased LRG1 directly potentiates TGF-β signaling in glomerular cells in an autocrine and paracrine manner to promote DKD, and indirectly via glomerular cross-talk.
2024-12-26 | GSE269534 | GEO
Project description:While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25-30% of diabetic patients still develop the disease. In the present work we adopted a system biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic mice (Ins2Akita) treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs’s signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthelonide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs’s signature. Treatment of diabetic Ins2Akita mice with dimethylaminoparthenolide (DMAPT), a water soluble analogue of parthenolide, significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD.
2020-09-17 | PXD018728 | Pride
Project description:To investigate the effect of LRG1 overexpression on gene expression of eWAT from db/db mice, we transduced 4-week-old db/db mice with AAV8-eGFP or AAV8-LRG1-FL and harvested eWAT at 7 weeks and 10 weeks of age. We then performed gene expression profiling analysis using data obtained from RNA-seq of eWAT from eGFP- and LRG1-overexpressing mice at two time points.
2022-07-18 | GSE208219 | GEO
Project description:We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli; 330 probesets were commonly differentially expressed in both compartments. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in an additional set of DKD samples. Affymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. Stringent statistical analysis using the Benjamini_Hochberg corrected 2-tailed t-test was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. This Series includes DKD and control glomeruli samples.
2011-08-02 | E-GEOD-30528 | biostudies-arrayexpress
Project description:We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli; 330 probesets were commonly differentially expressed in both compartments. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in an additional set of DKD samples. Affymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. Stringent statistical analysis using the Benjamini_Hochberg corrected 2-tailed t-test was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. This Series includes DKD and control tubuli samples.
2011-08-02 | E-GEOD-30529 | biostudies-arrayexpress
Project description:Leucine-rich-alpha-2-glycoprotein1 (LRG1), a highly conserved member of the leucine-rich repeat family of proteins, has been reported to be involved in several tumors. Previous studies showed that it has great importance in epithelial–mesenchymal transition in colorectal cancer and could promote glioma cell lines invasion and migration. Despite the intimate relationships between LRG1 and migration in cancer research, its role in wound repair or re-epithelialization has not been uncovered. So we dicided using keratinocytes to see its transcriptomes changing after LRG1 addition.
2019-11-11 | GSE122527 | GEO
Project description:Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Neutrophil extracellular traps (NETs) are a network structure composed of loose chromatin and embedded with multiple proteins. Here, we observed increased NETs deposition in the glomeruli of DKD patients and diabetic mice (streptozotocin-induced or db/db mice). After degrading NETs with DNase I, diabetic mice exhibited attenuated glomerulopathy and glomerular endothelial cell (GEC) injury. We also observed alleviated glomerulopathy and GEC injury in peptidylarginine deiminase 4 (PAD4)-knockout mice with streptozotocin-induced diabetes. In vitro, NET-induced GEC pyroptosis was characterized by pore formation in the cell membrane, dysregulation of multiple genes involved in cell membrane function, and high expression of pyroptosis-related proteins. Strengthening the GEC surface charge by oleylamine significantly inhibited NET-induced GEC pyroptosis. These results indicate that NET-induced alterations in GEC charge are associated with GEC pyroptosis in the pathogenesis of DKD and suggest that NETs are a potential therapeutic target for DKD.
2022-09-01 | GSE189875 | GEO
Project description:Deglycosylated-leucine-rich α-2-glycoprotein1 (DG-LRG1) as well as LRG1 was discovered to promote angiogenesis under diabetes mellitus condition through TGF-β independent binding to endoglin. To examine the signaling pathways triggered by DG-LRG1, we subjected whole-cell protein lysates of control and DG-LRG1 treated HUVECs to a Phospho Explorer antibody array analysis using commercial antibody array assay kit (Full Moon Biosystems, Inc.). Samples were probed against 1318 site-specific and phospho-specific antibodies with two replicates per antibody printed on a coated glass microscope slide. Phospho Explorer antibody array experiments and analyses were performed as a custom service by E-Biogen (Ebiogen Inc., Seoul, Republic of Korea).
2020-10-25 | GSE160005 | GEO
Project description:In order to find out the different expression of miRNA in DKD patients and controls, the kidney tissues of DKD and controls were used to do the miRNA mircroassy.
2024-06-30 | GSE179171 | GEO
Project description:Leucine-rich alpha-2 glycoprotein 1 (Lrg1) appears to be associated with the progression of cerebral ischemia-reperfusion injury, but its exact mechanism remains unknown. Here, we utilized scRNA-seq to compare the microenvironmental changes in the brains of Lrg1 knockout mice and wild-type mice following MCAO/R, in order to elucidate the role of Lrg1 after MCAO/R.
2023-12-06 | GSE245386 | GEO