Urinary single-cell sequencing captures intrarenal injury and repair processes in human acute kidney injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE199321 | GEO | 2022/08/24
REPOSITORIES: GEO
Similar Datasets
Project description:Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with an increased morbidity and mortality. Currently, no effective treatment options are available. Here, we show that glutamine significantly attenuates leukocyte recruitment and inflammatory signaling in human and murine tubular epithelial cells (TECs). In a murine AKI model induced by ischemia-reperfusion-injury (IRI) we show that glutamine causes transcriptomic and proteomic reprogramming in renal TECs and neutrophils, resulting in decreased epithelial apoptosis, neutrophil recruitment and improved mitochondrial functionality and respiration provoked by an ameliorated oxidative phosphorylation. We identify the proteins glutamine gamma glutamyltransferase 2 (Tgm2) and apoptosis signal-regulating kinase (Ask1) as the major targets of glutamine in apoptotic signaling. Increased Tgm2 expression and reduced Ask1 activation result in decreased JNK activation leading to a diminished mitochondrial intrinsic apoptosis in kidneys upon IRI-induced AKI and under hypoxia or following TNFα-treatment of TECs. Consequently, glutamine administration attenuated kidney injury in vivo during AKI progression as well as TEC viability in vitro under inflammatory and hypoxic conditions.
2023-03-11 | PXD029723 | Pride
Project description:Rhabdomyolysis is a severe condition caused by skeletal muscle damage, leading to acute kidney injury (AKI). We demonstrate that complement has a direct pathogenic role in rhabdomyolysis-induced AKI. Deposition of C3d in the tubules of patients and mice correlated with rhabdomyolysis-induced AKI. Moreover, C3-defiient mice with rhabdomyolysis had preserved renal function. Mechanistically, C3-deficiency attenuated strongly inflammatory and apoptotic components of the renal transcriptome, perturbed by rhabdomyolysis. Complement was activated intrarenal by the lectin pathway via collectin-11. It proceeded in a C4-bypass manner and was amplified by heme-activated alternative pathway. Therefore, complement and heme are promising therapeutic targets for rhabdomyolysis-induced AKI.
2020-11-01 | GSE153507 | GEO
Project description:Administration of exogenous mesenchymal stem cells (MSCs) has been shown to improve the recovery from acute kidney injury (AKI). It has been suggested that the beneficial effect of MSCs is related to the paracrine release of factors favouring proliferation of intrinsic epithelial cells survived to injury rather than to their trans-differentiation. However the factors involved remain to be determined. In the present study we demonstrated that microvesicles (MVs) derived from human bone marrow MSCs are able to stimulate in vitro proliferation and apoptosis resistance of tubular epithelial cells (TEC). In addition, MVs were found to accelerate in vivo the morphological and functional recovery of glycerol induced AKI in SCID mice by inducing TEC proliferation. The effect of MVs on the recovery of AKI was comparable to that of human MSC treatment. In vitro we found that the CD44 and beta1-integrin-dependent incorporation of MVs in TEC was required for their biological action. However, despite their internalization, RNase-treated MVs failed to induce in vitro apoptosis resistance and TEC proliferation, and in vivo recovery from AKI, suggesting an RNA-dependent biological effect. Microarray analysis and quantitative RT-PCR of MV-RNA extract indicated that MVs were shuttling a specific subset of cellular mRNA, such as mRNA associated with the mesenchymal differentiative phenotype and with several cell functions involved in the control of transcription, proliferation, apoptosis and cell immune regulation. These results suggest that MVs derived from MSCs may activate a proliferative program in TEC survived to injury in AKI by an horizontal transfer of mRNA.
2009-01-20 | GSE12243 | GEO
Project description:Objectives: Secretion of extracellular vesicles (EV) and associated micro-RNAs (miR) is altered during cellular stress and may serve as biomarkers of organ injury. We hypothesized that measuring changes in urinary levels of EV and miR will predict the onset of acute kidney injury in cardiac surgery patients. Design: Predictive accuracy biomarker study performed in the cohort of the REVAKI-2 trial Setting: Single center ICU between September 2015 and September 2018 Interventions: Intravenous sildenafil citrate 12.5 mg kg-1 over 150 min or dextrose 5% at the commencement of surgery. Measurements and main results: Urine samples were collected before and 24 hours after the procedure from 93 cardiac surgery patients. Urine EV concentrations and size distribution were assessed using NanoSight. EV derivation and levels were measured using flow cytometry. Samples from 10 selected patients were sequenced to detect differentially expressed miR. Verification was performed with advanced TaqMan assays in samples from all patients. Urine EV concentrations significantly increased in patients with AKI after surgery, with the percentage of EV positive for aquaporin-2 and β1-integrin also increasing. Pre surgery podocalyxin-positive EV were significantly lower, and β1-integrin EV werehigher in patients with AKI. The levels of the former correlated with the severity of theinjury. miR-125a-5p was expressed at higher levels in urine from patients with AKI stage 2/3. Levels of miR-10a-5p decreased after surgery in AKI patients; its levels correlated with the severity of the injury. Preoperative levels of podocalyxin EVs and miR-125a-5p had moderate AKI predictive value and, in a logistic model together with ICU lactate levels, offered good (AUC = 80.9%) AKI prediction. Conclusions: Lower levels of podocalyxin-positive EV at baseline predict the severity of post-surgery AKI. Urine EV concentrations and miR expression offer excellent predictive accuracy when combined with commonly measured biomarkers.
2022-02-26 | GSE197272 | GEO
Project description:Because exosomes have gained attention as a source of biomarkers, we investigated if miRNAs in exosomes (exo-miRs) can report the disease progression of organ injury. Using renal ischemia-reperfusion injury (IRI) as a model of acute kidney injury (AKI), we determined temporally-released exo-miRs in urine during IRI and found that these exo-miRs could reliably mirror the progression of AKI. From the longitudinal measurements of miRNA expression in kidney and urine, we found that release of exo-miRs was regulated sorting process, rather than simply representing their intracellular biosynthesis. In the injury state, miR-16, miR-24, and miR-200c were increased in the urine. Interestingly, expression of target mRNAs of these exo-miRs was significantly altered in renal medulla. Next, in the early recovery state, urinary exo-miRs (miR-9a, miR-141, miR-200a, miR-200c, miR-429), which shares Zeb1/2 as a common target mRNA, were upregulated, indicating that they reflect TGF--associated renal fibrosis. Finally, release of exo-miRs (miR-125a, miR-351) was regulated by TGF-1 and was able to differentiate the sham and IRI even after the injured kidneys were functionally recovered. Altogether, these data indicate that exo-miRs released in renal IRI are largely associated with TGF- signaling. Temporal release of exo-miRs which share targets might be a regulatory mechanism to control the disease progression of AKI.
2019-03-01 | GSE125305 | 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:Introduction: Renal ischemia-reperfusion (IR) causes acute kidney injury (AKI) with high mortality and morbidity. The objective of this study was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Methods: Left renal ischemia was induced in rats by clamping renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n=8/group) received Valproic Acid (150 mg/kg; VPA), Dexamethasone (3 mg/kg; Dex) or Vehicle (Saline) intraperitoneally. Animals were sacrificed at 3h, 24h or 120h post- IR and blood, urine and kidney were collected. Results: Serum creatinine (mg/dL) at 24 h IR in VPA (2.7±1.8) and Dex (2.3±1.2) was reduced (P<0.05) compared to Vehicle (3.8±0.5). At 3h post-IR, urine albumin (mg/ml) was higher in Vehicle (1.47±0.10), VPA (0.84±0.62) and Dex (1.04±0.73) compared to uninjured/untreated control (0.14±0.26) group. At 24h post-IR urine Lipocalin-2 (µg/ml) was significantly higher (P<0.05) in VPA, Dex and Vehicle groups (9.61-11.36) compared to uninjured/untreated control (0.67±o.29); also, Kidney Injury Molecule-1 (KIM-1; ng/ml) was significantly higher in VPA, Dex and Vehicle groups (13.7-18.7) compared uninjured/untreated control (1.7±1.9). KIM-1 levels were significantly (P<0.05) higher in all groups compared to uninjured/untreated control levels. Histopathology at 3h post IR demonstrated (P<0.05) reduction in ischemic injury in the renal cortex in VPA (Grade 1.6± 1.5) compared to Vehicle (Grade 2.9±1.1) group. Inflammatory cytokines IL1β and IL6 were down-regulated in VPA and Dex groups. BCL2 was higher in VPA group. DNA microarray analysis demonstrated reduced stress response and injury, and improved recovery related gene expression in the kidneys of VPA treated animals. Conclusions: VPA administration reduced kidney IR injury and improved regeneration. KIM-1 and Lipocalin-2 appear to be promising early urine biomarkers of acute ischemic kidney injury. We had three experimental groups. Group A, VPA treatment; Group B, Dexamethasone treatment; and Group C, No treatment (vehicle saline control). Treatments were administered prior to the induction of left renal ischemia. Animals underwent 45 minutes of left renal ischemia, followed by reperfusion, and right nephrectomy as described above. Following reperfusion, animals were sacrificed at 3, 24 or 120 hours (n=8/group). In the 3 hour group, rats were maintained under anesthesia after surgery until sacrifice. In the 24 and 120 hour groups, the rats were recovered and returned to the cages for normal housing. Analgesic buprenorphine (0.05mg/kg) was administered every 12 h for three days post-operatively. After animal sacrifice, urine, blood, and kidney were collected for kidney functional biomarker assays, histology and / or molecular analyses. Urine was obtained via cystocentesis and blood was obtained via the left renal vein. Tissue and urine samples collected from normal (naïve) animals (n=5) were used for baseline measurements. A subset of 46 animals (n = 4-5 per group) were selected for microarray analysis.
2015-07-06 | E-GEOD-58438 | biostudies-arrayexpress
Project description:The kidney has large regenerative capacity that is impeded when injured renal tubular epithelial cells (TECs) undergo SNAI1-driven partial epithelial mesenchymal transition (pEMT). Here we investigate the role of IL11 in TEC pEMT and kidney repair. Wild-type mice with acute kidney injury (AKI) upregulate IL11 in TECs triggering an ERK/P90RSK/GSK3β axis of SNAI1 expression leading to impaired renal function, which is abrogated in Il11 null mice. In mouse models of AKI, a neutralizing IL11 antibody promotes kidney regeneration, while attenuating pEMT, fibrosis and kidney dysfunction. In TECs, TGFβ1 induces autocrine IL11/ERK-dependent pEMT leading to paracrine, IL11-mediated fibroblast activation. Mice with TEC-specific deletion of Il11ra1 are protected from pEMT, inflammation, fibrosis and renal failure. In a mouse model of chronic kidney disease, administration of anti-IL11 reverses fibrosis, regenerates kidney parenchyma and restores renal function. Therapeutic inhibition of IL11 signaling appears permissive for promoting kidney regeneration and improving kidney function.
2022-11-17 | GSE199080 | GEO
Project description:Contrast-induced acute kidney injury (CI-AKI) is typically defined by an increase in serum creatinine (SCr) after intravascular administration of contrast medium. Since creatinine is an unreliable indicator for acute changes in kidney function, an early biomarkers for CI-AKI diagnosis is important for initiating therapy.We assessed the hypothesis that circulating microRNAs (miRNAs) could be served as potential biomarkers to early detect CI-AKI.The rat model of acute kidney injury was developed as we previously described. We first detect miRNA profile of plasma and kidney tissue using Agilent microarray platform. 3 miRNA species with > 1.5-fold increase in plasma samples of CI-AKI rats, including miRNA-30a, miRNA-30e and miRNA-188, were selected as candidate miRNAs of potential biomarkers. 24 rats were randomly divided into 2 groups (CI-AKI group and control group), each with 4 subgroups (n=3). Peripheral blood and kidney samples were harvest at 8h after contrast medium/normal saline administration. Total RNA sample from each rat in the same subgroup was combined together as pooled sample for further test. The Agilent microarray platform was adapted to profile the miRNA spectra.
2016-05-14 | E-GEOD-81400 | biostudies-arrayexpress
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