Profile of gene expression in experimental acute kidney injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE273063 | GEO | 2024/07/29
REPOSITORIES: GEO
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Project description:Treatment of acute kidney injury (AKI) is suboptimal. TWEAK is known to mediate cell death and inflammation in AKI. Transcriptomic analysis of murine tubular cells will allow us to identify novel mediators and therapeutic targets of this pathology. TWEAK is an inflammatory cytokine which is upregulated in AKI. Transcriptomic analysis of TWEAK-stimulated cultured murine tubular epithelial cells identified downregulation of peroxisome proliferator activated receptor-g coactivador-1a (PGC-1a) and its target genes (mitochondrial proteins Ndufs1, Sdha, and Tfam) as a shared feature.
2024-07-29 | GSE273064 | GEO
Project description:Chronic kidney disease (CKD) is the gradual, asymptomatic loss of kidney function and current tests only identify it when significant loss has already happened. Using RNA sequencing in a mouse model of folic acid (FA) induced nephropathy, here we report the identification of 10 genes that track kidney fibrosis development, the common pathological finding in CKD patients. The gene expression of all 10 candidates was confirmed to be significantly high (~ 10-150 fold) in three well-established and mechanistically distinct mouse models of kidney fibrosis. Protein expression was also high in the FA model as well as patients with biopsy-proven kidney fibrosis. The specificity of these 10 candidates for kidney fibrosis was demonstrated by showing a very modest (~ 2-5 fold) increase in the mouse models of acute kidney injury as well as following liver fibrosis in mice and humans. Using targeted selected reaction monitoring mass spectrometry (SRM-MS) we found that 3 out of 10, cadherin 11 (CDH11), mannose receptor C1 (MRC1), phospholipid transfer protein (PLTP), are detectable in human urine. Furthermore, the levels of CDH11 and MRC1 are able to distinguish patients with chronic kidney disease from healthy individuals (n = 78, p<0.01). In summary, we report the identification of CDH11 and MRC1 as novel non-invasive biomarkers of CKD. mRNA sequencing of mouse kidney before and at various time points (1,2,3,7 & 14 days) after intraperitoneal treatment with folic acid.
2015-10-23 | E-GEOD-65267 | biostudies-arrayexpress
Project description:18 zero-hour and 18 selected post-transplant (Tx) biopsy samples from 18 kidney allografts (8 acute kidney injury (AKI), 10 PBx - protocol biopsies - controls) were analyzed by using the Affymetrix GeneChipM-BM-. miRNA 3.0 Array. Comparison between control group (protocol biopsies) and indication biopsies with histological lesions of acute tubular necrosis without rejection (ATN).
2015-01-15 | E-GEOD-53771 | biostudies-arrayexpress
Project description:Hypertension and persistent activation of the renin-angiotensin system (RAS) are predisposing factors for development of acute kidney injury (AKI). Although bone marrow-derived stromal cells (BMSCs) have shown therapeutic promise in treatment of AKI, the impact of pathological RAS on BMSC functionality has remained unresolved. RAS and its local components in the bone marrow are involved in several key steps of cell maturation processes. This may also render BMSC population vulnerable to alterations even in the early phases of RAS pathology. We isolated TG-BMSCs from young, end organ disease-free rats with increased RAS activation (human angiotensinogen/renin double transgenic rats; dTGR) that eventually develop hypertension and die of end-organ damage and kidney failure at 8-weeks-of-age. Control cells were isolated from wild-type Sprague-Dawley rats (SD-BMSCs). Cell phenotype, mitochondrial reactive oxygen species (ROS) production and respiration were assessed, and gene expression profiling was carried out using microarrays. Cells’ therapeutic efficacy was evaluated in a rat model of acute ischemia-reperfusion-induced AKI. Serum urea and creatinine were measured at 24h and 48h. Acute tubular damage was scored and immunohistochemistry was used for evaluation for markers of inflammation (MCP-1, ED-1), and kidney injury (KIM-1, NGAL). TG-BMSCs showed distinct mitochondrial morphology, decreased cell respiration, and increased production of ROS. Gene expression profiling revealed a pronounced pro-inflammatory phenotype. In contrast to the therapeutic effect of SD-BMSCs, administration of TG-BMSCs in the AKI model resulted in exacerbation of kidney injury and high mortality. Our results demonstrate that early persistent RAS activation can dramatically compromise therapeutic potential of BMSCs by shift into a pro-inflammatory phenotype with mitochondrial dysfunction. A comparison of transcriptome of a bone marrow-derived stromal cells from a double-transgene rats compared to those from control rats
2014-03-31 | E-GEOD-51593 | biostudies-arrayexpress
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Project description:Chronic kidney disease (CKD) is the gradual, asymptomatic loss of kidney function and current tests only identify it when significant loss has already happened. Using RNA sequencing in a mouse model of folic acid (FA) induced nephropathy, here we report the identification of 10 genes that track kidney fibrosis development, the common pathological finding in CKD patients. The gene expression of all 10 candidates was confirmed to be significantly high (~ 10-150 fold) in three well-established and mechanistically distinct mouse models of kidney fibrosis. Protein expression was also high in the FA model as well as patients with biopsy-proven kidney fibrosis. The specificity of these 10 candidates for kidney fibrosis was demonstrated by showing a very modest (~ 2-5 fold) increase in the mouse models of acute kidney injury as well as following liver fibrosis in mice and humans. Using targeted selected reaction monitoring mass spectrometry (SRM-MS) we found that 3 out of 10, cadherin 11 (CDH11), mannose receptor C1 (MRC1), phospholipid transfer protein (PLTP), are detectable in human urine. Furthermore, the levels of CDH11 and MRC1 are able to distinguish patients with chronic kidney disease from healthy individuals (n = 78, p<0.01). In summary, we report the identification of CDH11 and MRC1 as novel non-invasive biomarkers of CKD.
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Project description:Renal fibrosis is the common pathway in the progression of chronic kidney disease (CKD). Acyloxyacyl hydrolase (AOAH) is expressed in various phagocytes and is highly expressed in proximal tubular epithelial cells (PTECs). Research shows that AOAH plays a critical role in infections and chronic inflammatory diseases, although its role in kidney injury is unknown. Here, we found that AOAH deletion led to exacerbated kidney injury and fibrosis after folic acid (FA) administration, which was reversed by overexpression of Aoah in kidneys. ScRNA-seq revealed that Aoah-/- mice exhibited increased subpopulation of CD74+ PTECs, though the percentage of total PTECs were decreased compared to WT mice after FA treatment. Additionally, exacerbated kidney injury and fibrosis seen in Aoah-/- mice was attenuated via administration of methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), an inhibitor of macrophage inhibition factor (MIF) and CD74 binding. Finally, AOAH expression was found positively correlated with estimated glomerular filtration rate while negatively correlated with the degree of renal fibrosis in kidneys of CKD patients. Thus, our work indicates that AOAH protects against kidney injury and fibrosis by inhibiting renal tubular epithelial cells CD74 signaling pathways. Targeting kidney AOAH represents a promising strategy to prevent renal fibrosis progression.
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Project description:Treatments for kidney fibrosis represent an urgent yet unmet clinical need. Effective therapies are limited due to not well understood molecular pathogenesis. We aimed at generating a comprehensive and integrated multi-omics data set (RNA/ microRNA transcriptomics and proteomics) of fibrotic kidneys which will be searchable through a user-friendly web application. Therefore, two commonly used mouse models were utilized: a reversible chemical-induced injury model (folic acid (FA) induced nephropathy) and an irreversible surgical-induced fibrosis model (unilateral ureteral obstruction (UUO)). RNA and small RNA sequencing as well as MS/MS with 10-plex tandem mass tags proteomics were performed with kidney samples from different time points over the course of fibrosis development. In summary, we present temporal and integrated multi-omics data from fibrotic mouse kidneys which are accessible through an interrogation tool to provide a searchable transcriptome and proteome for kidney fibrosis researcher.
2019-05-09 | PXD010861 | Pride
Project description:Treatments for kidney fibrosis represent an urgent yet unmet clinical need. Effective therapies are limited due to not well understood molecular pathogenesis. We aimed at generating a comprehensive and integrated multi-omics data set (RNA/ microRNA transcriptomics and proteomics) of fibrotic kidneys which will be searchable through a user-friendly web application. Therefore, two commonly used mouse models were utilized: a reversible chemical-induced injury model (folic acid (FA) induced nephropathy) and an irreversible surgical-induced fibrosis model (unilateral ureteral obstruction (UUO)). RNA and small RNA sequencing as well as MS/MS with 10-plex tandem mass tags proteomics were performed with kidney samples from different time points over the course of fibrosis development. In summary, we present temporal and integrated multi-omics data from fibrotic mouse kidneys which are accessible through an interrogation tool to provide a searchable transcriptome and proteome for kidney fibrosis researcher.
2019-05-09 | PXD011453 | Pride
Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.
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