Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genetic Susceptibility to Diabetic Nephropathy is Related to Pro-inflammatory Pathways

ABSTRACT: Diabetic nephropathy (DN) is a leading cause of ESRD worldwide, but its molecular pathogenesis is not well-defined and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. Here we describe a new mouse model, combining type 1 diabetes with activation of the renin angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy. The 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice with albuminuria but without detectable alterations in glomerular structure . We find dramatic difference in regulation of immune and inflammatory pathways with up-regulation of pro-inflammatory pathways in the susceptible (129) strain and coordinate down-regulation in the resistant (C57BL/6) strain, compared to their respective baselines. Many of these pathways were also up-regulated in a rat model and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and hypertension, may be critical early determinants of susceptibility to DN.

ORGANISM(S): Mus musculus

PROVIDER: GSE85569 | GEO | 2016/08/13

SECONDARY ACCESSION(S): PRJNA338806

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Genetic Susceptibility to Diabetic Nephropathy is Related to Pro-inflammatory Pathways

Project description:Diabetic nephropathy (DN) is a leading cause of ESRD worldwide, but its molecular pathogenesis is not well-defined and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. Here we describe a new mouse model, combining type 1 diabetes with activation of the renin angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy. The 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice with albuminuria but without detectable alterations in glomerular structure. We find dramatic difference in regulation of immune and inflammatory pathways with up-regulation of pro-inflammatory pathways in the susceptible (129) strain and coordinate down-regulation in the resistant (C57BL/6) strain, compared to their respective baselines. Many of these pathways were also up-regulated in a rat model and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and hypertension, may be critical early determinants of susceptibility to DN. The analysis was carried out on 2 strains of mice (129/SvEv and C57BL/6), each involving 2 genotypes (wild-type and RenTg/Ins2Akita mutations). Four replicates were used for each strain-genotype (with the exception of 129/SvEv wild-type mice, which had 3 replicates).

2016-08-13 | E-GEOD-85569 | biostudies-arrayexpress

Abnormal lactate metabolism is linked to albuminuria and kidney injury in diabetic nephropathy

Project description:Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease worldwide. Susceptibility to DN is inherited but genetic determinants of DN have not been precisely defined. We have previously described a mouse model combining genetic type 1 diabetes (Akita) with a renin transgene (ReninTg) that exhibits characteristic features of human DN including albuminuria, glomerulosclerosis, and genetic predisposition for kidney disease. We performed single-cell sequencing (10x Chromium) of glomerular cell suspensions obtained from the wildtype (WT) and Akita- ReninTg (AR) mice at 10 weeks of age before overt pathological abnormalities are present in kdiney.

2023-09-25 | GSE243995 | GEO

Transcriptome analysis identifies oxidative stress injury biomarkers for Diabetic Nephropathy

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

Hyperactivation of YAP/TAZ drives alterations in mesangial cells through stabilization of N-MYC in diabetic nephropathy

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

Dynaimic changes in glomerular cells in the development of diabetes

Project description:To investigate dynamic changes in glomerular cells, including podocyte, mesangial cells and glomerular endothelial cells, in the development of diabetic nephropathy We then performed gene expression profiling analysis using data obtained from RNA-seq of glomerular cells of control(m/m), diabetic (db-/- 6-week-old) and diabetic nephropathy (db-/- 10-week-old with albuminuria) mice

2023-10-27 | GSE219268 | GEO

Glomerular Transcriptome Profiling Comparing DBA/2 and C57BL/6 mice

Project description:Comparing glomerular gene expression level between mice with different susceptibilities to diabetic nephropathy, DBA/2 (susceptible) and C57BL/6 (resistant) mice, respectively. The hypothesis is that differential expression of glomerular genes regulate susceptibility to diabetic nephropathy. The results show immune related genes. Thus, glomerular inflammation may increase susceptibility to diabetic nephropathy in mice.

2016-07-22 | GSE84663 | GEO

Glomerular Transcriptome Profiling Comparing DBA/2 and C57BL/6 mice

2016-07-22 | E-GEOD-84663 | biostudies-arrayexpress

Differential Expression of Ove26(Diabetic) vs FVB(Nondiabetic) mice

Project description:Objective – Previous studies showed that genetic deletion or pharmacological blockade of the Receptor for Advanced Glycation Endproducts (RAGE) prevents the early structural changes in the glomerulus associated with diabetic nephropathy (DN). To overcome limitations of mouse models that lack the progressive glomerulosclerosis observed in humans, we studied the contribution of RAGE to DN in the OVE26 type 1 mouse, a model of progressive glomerulosclerosis and decline of renal function. Research Design and Methods – We bred OVE26 mice with homozygous RAGE knock out (RKO) mice and examined structural changes associated with DN and used inulin clearance studies and albumin:creatinine measurements to assess renal function. Affymetrix Mouse 430.2 microarrays were used to measure the differential expression of OVE26vsFVB(WT) mice. Transcriptional changes in the TGF-?1 and Plasminogen activator inhibitor 1 gene products were measured by pcr to investigate mechanisms underlying accumulation of mesangial matrix in OVE26 mice. Results - Deletion of RAGE in OVE26 mice reduced nephromegaly, mesangial sclerosis, cast formation, glomerular basement membrane thickening, podocyte effacement, and albuminuria. The significant 29% reduction in glomerular filtration rate observed in OVE26 mice was completely prevented by deletion of RAGE. Increased transcription of the genes for Plasminogen activator inhibitor 1, TGF-?1, TGF-? induced, ?1- (IV) collagen observed in OVE26 renal cortex significantly reduced in OVE26 RKO kidney cortex. ROCK1 activity was significantly lower in OVE26 RKO compared to OVE26 kidney cortex. Conclusions - These data provide compelling evidence for critical roles for RAGE in the pathogenesis of DN and suggest that strategies targeting RAGE in long-term diabetes may prevent loss of renal function. The differential gene expression of OVE26 (diabetics) vs FVB (nodiabetic WT) mice was measured using Affymetrix Mouse 430.2 arrays.

2011-02-22 | E-GEOD-20844 | biostudies-arrayexpress

Cross-species transcriptional networks in Diabetic Glomerulopathy in mouse and man

Project description:Murine models have been valuable instruments in defining the pathogenesis of diabetic nephropathy (DN), but they only partially recapitulate disease manifestations of human DN, limiting their utility . In order to define the molecular similarities and differences between human and murine DN, we performed a cross-species comparison of glomerular transcriptional networks. Glomerular gene expression was profiled in patients with early type 2 DN and in three mouse models (streptozotocin DBA/2 mice, db/db C57BLKS, and eNOS-deficient C57BLKS db/db mice). Species-specific transcriptional networks were generated and compared with a novel network-matching algorithm. Three shared, human-mouse cross-species glomerular transcriptional networks containing 143 (Human-STZ), 97 (Human- db/db), and 162 (Human- eNOS-/- db/db) gene nodes were generated. Shared nodes across all networks reflected established pathogenic mechanisms of diabetic complications, such as elements of JAK-STAT and VEGFR signaling pathways . In addition, novel pathways not formally associated with DN and cross-species gene nodes and pathways unique to each of the human-mouse networks were discovered. The human-mouse shared glomerular transcriptional networks will assist DN researchers in the selection of mouse models most relevant to the human disease process of interest. Moreover, they will allow identification of new pathways shared between mice and humans. We used microarrays to analyze the transcriptome of three different diabetic mouse models Glomerular RNA was extracted using the RNeasy Mini Kit and processed for hybridization on Affymetrix GeneChip Mouse Genome 430 2.0 microarrays.

2012-12-10 | E-GEOD-33744 | biostudies-arrayexpress

Expression date from db/db mice with or without treatment of traditional Chinese medicine Tang-shen Formula

Project description:The Chinese herbal granule Tangshen Formula (TSF) has been proven to decrease proteinuria and improve estimated glomerular filtration rate (eGFR) in diabetic kidney disease (DKD) patients with albuminuria. Nevertheless, little was known on the underlying mechanisms of TSF on treating DN. We used microarrays to detail to explore the target genes of TSF in the treatment of DN.

2017-01-25 | GSE90842 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data