Sepsis-Associated Acute Kidney Injury Induces Microvascular Compartment-Specific MicroRNA Changes
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ABSTRACT:
PROVIDER: PRJNA934507 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23441200.fastq.gz | Fastqsanger.gz | |||
| SRR23441300.fastq.gz | Fastqsanger.gz | |||
| SRR23441201.fastq.gz | Fastqsanger.gz | |||
| SRR23441301.fastq.gz | Fastqsanger.gz | |||
| SRR23441202.fastq.gz | Fastqsanger.gz |
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Project description:summary to be provided
2023-12-31 | GSE225193 | GEO
Project description:# Background Acute kidney injury (AKI) in sepsis patients increases patient mortality. Endothelial cells are important players in the pathophysiology of sepsis-associated AKI (SA-AKI), yet knowledge regarding their spatiotemporal involvement in coagulation disbalance and leukocyte recruitment is lacking. This study investigated the identity and kinetics of responses of different microvascular compartments in kidney cortex in response to SA-AKI. # Methods Laser microdissected arterioles, glomeruli, peritubular capillaries, and postcapillary venules from kidneys of mice subjected to cecal ligation and puncture (CLP) were analyzed using RNA sequencing. Differential expression and pathway enrichment analyses identified genes involved in coagulation and inflammation. A selection of these genes was evaluated by RT-qPCR in microvascular compartments of renal biopsies from patients with SA-AKI. The role of two identified genes in lipopolysaccharide-induced endothelial coagulation and inflammatory activation were determined in vitro in HUVEC using siRNA-based gene silencing. # Results CLP-sepsis in mice induced altered expression of approximately 400 genes in the renal microvasculature, with microvascular compartments exhibiting unique spatiotemporal responses. In mice, changes in gene expression related to coagulation and inflammation were most extensive in glomeruli at early and intermediate time points, with high induction of Plat, Serpine1, Thbd, Icam1, Stat3, and Ifitm3. In human SA-AKI, PROCR and STAT3 were induced in postcapillary venules, while SERPINE1 expression was diminished. IFITM3 was increased in arterioles and glomeruli. In vitro studies revealed that STAT3 and IFITM3 partly control endothelial coagulation and inflammatory activation. # Conclusion Renal microvascular compartments in mice and humans exhibited heterogeneous changes in coagulation- and inflammation-related gene expression in response to SA-AKI. Additional research should aim at understanding the functional consequences of the here described heterogeneous microvascular responses to establish the usefulness of identified genes as therapeutic targets in SA-AKI.
2023-12-31 | GSE225192 | GEO
Project description:Sepsis-Associated Coagulation and Inflammation are Differentially Regulated in Renal Microvascular Beds
| PRJNA934322 | ENA
Project description:Endothelial cells in the blood vessels in the kidney exert different functions depending on the (micro)vascular bed they are located in. These functional differences are likely a result of differential microRNA and mRNA transcription patterns, yet the identity of these molecules is not well known. We zoomed in on the endothelial cells of microvascular compartments in mouse renal cortex by laser microdissecting the microvessels prior to (small) RNA sequencing analyses. By these means, we characterised microRNA and mRNA transcription profiles of arterioles, glomeruli, peritubular capillaries, and post-capillary venules. RT-qPCR, in situ hybridisation, and immunohistochemistry were used to validate sequencing results. Unique microRNA and mRNA transcription profiles were found in all microvascular compartments, with dedicated marker microRNAs and mRNAs showing enriched transcription in a single microvascular compartment. In situ hybridisation validated localisation of microRNAs mmu-miR-140-3p in arterioles, of mmu-miR-322-3p in glomeruli, and of mmu-miR-451a in post-capillary venules. Immunohistochemical staining showed that von Willebrand Factor protein was mainly expressed in arterioles and post-capillary venules, while GABRB1 expression was enriched in glomeruli and IGF1 in post-capillary venules. Our study shows that microvascular endothelial heterogeneity in mouse kidney is a result of a combination of differentially expressed microRNAs and mRNAs. The identified profiles provide important molecular information to take into account for future studies into microvascular engagement in health and disease.
2023-06-30 | GSE220985 | GEO
Project description:Endothelial cells in the blood vessels in the kidney exert different functions depending on the (micro)vascular bed they are located in. These functional differences are likely a result of differential microRNA and mRNA transcription patterns, yet the identity of these molecules is not well known. We zoomed in on the endothelial cells of microvascular compartments in mouse renal cortex by laser microdissecting the microvessels prior to (small) RNA sequencing analyses. By these means, we characterised microRNA and mRNA transcription profiles of arterioles, glomeruli, peritubular capillaries, and post-capillary venules. RT-qPCR, in situ hybridisation, and immunohistochemistry were used to validate sequencing results. Unique microRNA and mRNA transcription profiles were found in all microvascular compartments, with dedicated marker microRNAs and mRNAs showing enriched transcription in a single microvascular compartment. In situ hybridisation validated localisation of microRNAs mmu-miR-140-3p in arterioles, of mmu-miR-322-3p in glomeruli, and of mmu-miR-451a in post-capillary venules. Immunohistochemical staining showed that von Willebrand Factor protein was mainly expressed in arterioles and post-capillary venules, while GABRB1 expression was enriched in glomeruli and IGF1 in post-capillary venules. Our study shows that microvascular endothelial heterogeneity in mouse kidney is a result of a combination of differentially expressed microRNAs and mRNAs. The identified profiles provide important molecular information to take into account for future studies into microvascular engagement in health and disease.
2023-06-30 | GSE220986 | GEO
Project description:WNT Pathway Signalling in Kidney Transplants with Microvascular Injury
| PRJNA476707 | ENA
Project description:Sepsis-induced acute kidney injury (S-AKI) is the most common complication in hospitalized and critically ill patients, highlighted by a rapid decline of kidney function occurring a few hours or days after sepsis onset. Systemic inflammation elicited by microbial infections is believed to lead to kidney damage under immunocompromised conditions. However, while AKI has been recognized as a disease with long-term sequelae, partly due to the associated higher risk of chronic kidney disease (CKD), the understanding of kidney pathophysiology at the molecular level and the global view of dynamic regulations in situ after S-AKI, including the transition to CKD, remains limited. Existing studies of S-AKI mainly focus on deriving sepsis biomarkers from body fluids. In the present study, we constructed a mid-severity septic murine model using cecal ligation and puncture (CLP), and examined the temporal changes to the kidney proteome and phosphoproteome at day 2 and day 7 after CLP surgery, corresponding to S-AKI and the transition to CKD, respectively, by employing an ultrafast and economical filter-based sample processing method combined with the label-free quantitation approach. Collectively, we identified 2,119 proteins and 2,950 phosphosites through multi-proteomics analyses. Among them, we identified an array of highly promising candidate marker proteins indicative of disease onset and progression accompanied by immunoblot validations, and further denoted the pathways that are specifically responsive to S-AKI and its transition to CKD, which include regulation of cell metabolism regulation, oxidative stress, and energy consumption in the diseased kidneys. Our data can serve as an enriched resource for the identification of mechanisms and biomarkers for sepsis-induced kidney diseases.
| MSV000086126 | MassIVE
Project description:Kidney transplant recipients with biopsy-proven microvascular injury (MVI) have increased risk for allograft failure. MVI is often caused by antibody-mediated injury that is resistant to available treatments. Current diagnostic methods are also inadequate, with interobserver variability in traditional pathology reads, variable assessment of circulating donor-specific antibody between HLA laboratories, and peritubular capillary C4d staining. Molecular assessments of kidney biopsies can provide improved sensitivity for diagnosing MVI and other allograft pathology, while improving reproducibility and objectivity. Most molecular classifiers have been based on whole genome sequencing to develop diagnostic tests, but have provided limited therapeutic targets. In this study, we pursued a candidate gene approach to measure WNT pathway genes in residual clinical FFPE biopsies with and without MVI. We focused on the WNT pathway because of previous translational studies that implicated this pathway in chronic renal allograft injury as well as vascular injury in native chronic kidney disease. Case-control study of 95 residual FFPE biopsies with MVI (g+ptc score >= 2, n=50) or Stable (g+ptc score < 2 and no other major abnormalities, n=45). Biopsies were retrieved from a biorepository of over 500 kidney transplant biopsies. We compared expression of 180 WNT pathway genes and 30 custom skipe-in targets (derived from previous studies of endothelial injury in transplantation) between MVI and Stable groups, with correction for multiple comparisons using FDR < 5%. This dataset is part of the TransQST collection.
2019-06-15 | E-GEOD-115989 | biostudies-arrayexpress
Project description:Kidney transplant recipients with biopsy-proven microvascular injury (MVI) have increased risk for allograft failure. MVI is often caused by antibody-mediated injury that is resistant to available treatments. Current diagnostic methods are also inadequate, with interobserver variability in traditional pathology reads, variable assessment of circulating donor-specific antibody between HLA laboratories, and peritubular capillary C4d staining. Molecular assessments of kidney biopsies can provide improved sensitivity for diagnosing MVI and other allograft pathology, while improving reproducibility and objectivity. Most molecular classifiers have been based on whole genome sequencing to develop diagnostic tests, but have provided limited therapeutic targets. In this study, we pursued a candidate gene approach to measure WNT pathway genes in residual clinical FFPE biopsies with and without MVI. We focused on the WNT pathway because of previous translational studies that implicated this pathway in chronic renal allograft injury as well as vascular injury in native chronic kidney disease.
2019-06-15 | GSE115989 | GEO
Project description:Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life threatening sequalae attributed to sepsis. Mechanistically, SA-AKI is a consequence of unabated myeloid cell activation and oxidative stress that induces tubular injury. Iron mediates inflammatory pathways directly and through regulating the expression of myeloid-derived ferritin, an iron storage protein comprised of ferritin light (FtL) and ferritin heavy chain (FtH) subunits. Previous work revealed myeloid FtH deletion leads to a compensatory increase in intracellular and circulating FtL and is associated with amelioration of SA-AKI. We designed this study to test the hypothesis that loss of myeloid FtL and subsequently, circulating FtL will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse (FtLLysM-/-) and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, serum ferritin levels were significantly lower in the knockout mice, suggesting that myeloid cells dominantly contribute to circulating ferritin. Interestingly, while sepsis induction led to a marked production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function, as evident by a rise in serum creatinine and cystatin C, and renal injury identified by expression of kidney injury molecule-1 and neutrophil gelatinase associated lipocalin. Finally, RNA sequencing revealed upregulation of pathways for cell cycle arrest and autophagy post-sepsis, but no significant differences were observed between genotypes, including in key genes associated with ferroptosis, an iron-mediated form of cell death. The loss of FtL did not impact sepsis-mediated activation of NFkB or HIF-1a signaling, key inflammatory pathways associated with dysregulated host response. Taken together, while FtL overexpression was shown to be protective against sepsis, loss of FtL did not influence sepsis pathogenesis.
2024-05-13 | GSE255281 | GEO