Effect of PTBA on acute kidney injury during AKI
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE126418 | GEO | 2019/03/25
REPOSITORIES: GEO
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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 Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.
2013-09-05 | E-GEOD-44925 | biostudies-arrayexpress
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.
2013-09-05 | GSE44925 | GEO
Project description:Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers. AKI biopsies sample names and CEL files are from GSE21374. All consenting renal transplant patients undergoing biopsies for cause as standard of care between 09/2004 and 10/2007 at the university of Alberta or between 11/2006 and 02/2007 at the University of Illinois were included in the analysis. In addition to the cores required for standard histopathology, we collected one core for gene expression studies. the relationship between gene expression in the biopsy and subsequent graft loss was analyzed. This dataset is part of the TransQST collection.
2012-02-21 | E-GEOD-30718 | biostudies-arrayexpress
Project description:Acute kidney injury (AKI) is associated with an increased risk of chronic kidney disease (CKD). To extend our understanding of renal repair, and its limits, we performed a detailed molecular characterization of a murine ischemia reperfusion injury (IRI) model for 12 months post injury. RNA-seq analysis highlights a cascade of temporal specific gene expression patterns related to tubular injury/repair, fibrosis, innate and adaptive immunity.
2017-09-12 | GSE98622 | GEO
Project description:Ischemic acute kidney injury (AKI), a complication that frequently occurs in hospital settings, is often associated with hemodynamic compromise, sepsis, cardiac surgery or exposure to nephrotoxicants. AKI is associated with immune cell infiltration into the kidney stroma, which causes acute tubular injury. Here, using a murine renal ischemic-reperfusion injury (IRI) model we show that intercalated cells (ICs) rapidly adopt a pro-inflammatory phenotype post IRI. During the early phase of AKI, we demonstrate that either blocking the pro-inflammatory P2Y14 receptor located on the apical membrane of ICs, or ablation of the gene encoding the P2Y14 receptor in ICs: 1) inhibits IRI-induced chemokine expression increase in ICs; 2) reduces neutrophil and monocyte renal infiltration; 3) reduces the extent of kidney dysfunction; and 4) attenuates proximal tubule (PT) damage. These observations indicate that the P2Y14 receptor participates in the very first inflammatory steps associated with ischemic AKI. In addition, we show that the concentration of the P2Y14 receptor ligand, uridine diphosphate-glucose (UDP-Glc), is higher in urine samples from intensive care unit patients who developed AKI when compared with urine from patients without AKI. In particular, we observed a strong correlation between UDP-Glc concentration and the development of AKI in cardiac surgery patients. Our study identifies the UDP-Glc/P2Y14 receptor axis as a potential target for the prevention and/or attenuation of ischemic-AKI.
2020-03-17 | GSE144522 | GEO
Project description:The availability of mesenchymal stem cells in kidney injury repair has been demonstrated. However, the underlying molecular mechanism remains not well understood. Herein, we profiled the altered microRNAs in renal tissiues from cisplatin-induced acute kidney injury (AKI) rats administrated with or without rat bone marrow mesenchymal stem cells, normal kidneys as control. Sprague Dawley rats were administrated with PBS by caudal vein after 24h peritoneal injection of 6mg/mg cisplatin, short for g2. 1×106 MSCs were injected to rats after 24h peritoneal injection of cisplatin, short for g3. Kidneys from healthey rats were used as control, short for g1. Renal tissues were collected at day 5 after treatment. There were 44 micorRNAs changed with significance between g2 and g3, among which 36 microRNAs upregulated and 8 microRNAs downregulated.
2015-03-11 | GSE66761 | GEO
Project description:We constructed single-cell atlases of AKI induced by different etiologies, revealed potential homogeneity of injury patterns and heterogeneity between models in AKI. Extensive cell death and cytoskeletal remodeling events in proximal tubular cells (PTCs) as well as aberrant proliferation and inflammation of endothelial cells (ECs) in AKI are common injury patterns across different AKI models. However, there are differences in injury outcomes in PTCs with different etiologies, and ECs also have distinct transcriptional profiles.
2022-04-30 | GSE197266 | GEO
Project description:Since septic AKI is a common type of AKI in ICU, we need to understand the differences in renal RNA expression in septic kidney injury. Therefore, we used lipopolysaccharide intraperitoneal injection to construct a mouse model of septic renal injury, and verified that the model was successful, then RNA sequencing was performed. To know the difference of RNA expression through the comparison of kidney sequencing between the normal group and the septic AKI group.
2023-04-03 | GSE227623 | GEO
Project description:CD4+ T cells mediate the pathogenesis of ischemic and nephrotoxic acute kidney injury (AKI), as well as acute injury to other organs. However, the underlying mechanisms of CD4+ T cell-mediated pathogenesis are largely unknown. We therefore conducted unbiased RNA-sequencing to discover novel mechanistic pathways of kidney CD4+ T cells post-ischemia compared to normal mouse kidney. Unexpectedly, lipocalin-2 (Lcn2) gene, which encodes neutrophil gelatinase-associated lipocalin (NGAL) had the highest (~60)-fold increase. The NGAL increase in CD4+ T cells during AKI was confirmed at the mRNA level with real-time PCR and at the protein level with ELISA. NGAL is a potential biomarker for the early detection of AKI and has multiple potential biological functions during organ injury. However, the role of NGAL produced by CD4+ T cells has not been investigated. We found that ischemic AKI in NGAL knockout (KO) mice had worse renal outcomes compared to wild type (WT) mice. Adoptive transfer of NGAL-deficient CD4+ T cells from NGAL KO mice into CD4 KO or WT mice led to worse renal function than transfer of WT CD4+ T cells. In vitro simulated ischemia reperfusion showed that NGAL-deficient CD4+ T cells express higher levels of IFN-γ mRNA compared to WT CD4+ T cells. In vitro differentiation of naive CD4+ T cells to Th17, Th1 and Th2 cells led to significant increase in Lcn2 expression. Human kidney CD4+ T cell NGAL also increased significantly post-ischemia. These results demonstrate an important role for CD4+ T cell NGAL as a mechanism by which CD4+ T cells mediate AKI and extend the importance of NGAL in AKI beyond diagnostics.
2019-11-25 | GSE139171 | GEO
Project description:Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers.
2012-02-21 | GSE30718 | GEO