scholarly journals Comprehensive Molecular and Cellular Characterization of Acute Kidney Injury Progression to Renal Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Renyan Wu ◽  
Jiawei Li ◽  
Guowei Tu ◽  
Ying Su ◽  
Xuepeng Zhang ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Renal Fibrosis ◽  
Cell Activation ◽  
Acid Metabolism ◽  
Kidney Injury ◽  
Arachidonic Acid Metabolism ◽  
Metabolic Process ◽  
Fibrosis Progression ◽  
Molecular Features ◽  
Single Cell Rna Sequencing

Acute kidney injury (AKI) and chronic kidney disease (CKD) represent different stages of renal failure; thus, CKD can be regarded as a result of AKI deterioration. Previous studies have demonstrated that immune cell infiltration, oxidative stress, and metabolic mentalism can support renal fibrosis progression in AKI cases. However, the most important triggers and cell types involved in this pathological progression remain unclear. This study was conducted to shed light into the underlying cellular and molecular features of renal fibrosis progression through the analysis of three mouse whole kidney and one human single-cell RNA-sequencing datasets publicly available. According to the different causes of AKI (ischemia reperfusion injury [IRI] or cisplatin), the mouse samples were divided into the CIU [control-IRI-unilateral ureteral obstruction (UUO)] and CCU (control-cisplatin-UUO) groups. Comparisons between groups revealed eight different modules of differentially expressed genes (DEGs). A total of 1,214 genes showed the same expression pattern in both CIU and CCU groups; however, 1,816 and 1,308 genes were expressed specifically in the CCU and CIU groups, respectively. Further assessment of the DEGs according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway and Gene Ontology (GO) showed that T-cell activation, fatty acid metabolic process, and arachidonic acid metabolism were involved in the fibrosis progression in CIU and CCU. Single-cell RNA-sequencing data along with the collected DEGs information also revealed that the T-cell activation mainly happened in immune cells, whereas the fatty acid metabolic process and arachidonic acid metabolism occurred in tubule cells. Taken together, these findings suggest that the fibrosis process differed between the CIU and CCU stages, in which immune and tubule cells have different functions. These identified cellular and molecular features of the different stages of fibrosis progression may pave the way for exploring novel potential therapeutic strategies in the clinic.

CD28 deficiency attenuates primary blast-induced renal injury in mice via the PI3K/Akt signalling pathway

2019 ◽  
Vol 166 (E) ◽  
pp. e66-e69 ◽  
Author(s):  
Ying Liu ◽  
Y E Liu ◽  
C C Tong ◽  
P F Cong ◽  
X Y Shi ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Renal Injury ◽  
Cell Activation ◽  
Kidney Injury ◽  
Blast Injury ◽  
Signalling Pathway ◽  
Inflammatory Factors ◽  
Immunofluorescence Analysis ◽  
Primary Blast ◽  
Custom Made

IntroductionPrimary blast affects the kidneys due to direct shock wave damage and the production of proinflammatory cytokines without effective treatment. CD28 has been reported to be involved in regulating T cell activation and secretion of inflammatory cytokines. The aim of this study was to investigate the influence of primary blast on the kidney and the effect of CD28 in mice.MethodsA mouse model of primary blast-induced kidney injury was established using a custom-made explosive device. The severity of kidney injury was investigated by H&E staining. ELISA was applied to study serum inflammation factors’ expression. Western blot assays were used to analyse the primary blast-induced inflammatory factors’ expression in the kidney. Immunofluorescence analysis was used to examine the PI3K/Akt signalling pathway.ResultsHistological examination demonstrated that compared with the primary blast group, CD28 deficiency caused a significant decrease in the severity of the primary blast-induced renal injury. Moreover, ELISA and western blotting revealed that CD28 deficiency significantly reduced the levels of interleukin (IL)-1β, IL-4 and IL-6, and increased the IL-10 level (p<0.05). Finally, immunofluorescence analysis indicated that PI3K/Akt expression also changed.ConclusionsCD28 deficiency had protective effects on primary blast-induced kidney injury via the PI3K/Akt signalling pathway. These findings improve the knowledge on primary blast injury and provide theoretical basis for primary blast injury treatment.

Flt3 inhibition alleviates chronic kidney disease by suppressing CD103+ dendritic cell-mediated T cell activation

2018 ◽  
Vol 34 (11) ◽  
pp. 1853-1863 ◽  
Author(s):  
Ruifeng Wang ◽  
Titi Chen ◽  
Chengshi Wang ◽  
Zhiqiang Zhang ◽  
Xin Maggie Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
T Cells ◽  
T Cell ◽  
Kidney Disease ◽  
T Cell Activation ◽  
Cell Activation ◽  
Kidney Injury ◽  
Public Health Problem ◽  
Global Public Health ◽  
Flt3 Inhibitor

Abstract Background Chronic kidney disease (CKD) is a global public health problem, which lacks effective treatment. Previously, we have shown that CD103+ dendritic cells (DCs) are pathogenic in adriamycin nephropathy (AN), a model of human focal segmental glomerulosclerosis (FSGS). Fms-like tyrosine kinase 3 (Flt3) is a receptor that is expressed with high specificity on tissue resident CD103+ DCs. Methods To test the effect on CD103+ DCs and kidney injury of inhibition of Flt3, we used a selective Flt3 inhibitor (AC220) to treat mice with AN. Results Human CD141+ DCs, homologous to murine CD103+ DCs, were significantly increased in patients with FSGS. The number of kidney CD103+ DCs, but not CD103− DCs or plasmacytoid DCs, was significantly decreased in AN mice after AC220 administration. Treatment with AC220 significantly improved kidney function and reduced kidney injury and fibrosis in AN mice. AC220-treated AN mice had decreased levels of inflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, CCL2 and CCL5 and reduced kidney infiltration of CD4 T cells and CD8 T cells. The protective effect of AC220 was associated with its suppression of CD103+ DCs-mediated CD8 T cell proliferation and activation in AN mice. Conclusion Flt3 inhibitor AC220 effectively reduced kidney injury in AN mice, suggesting that this inhibitor might be a useful pharmaceutical agent to treat CKD.

scholarly journals Reclassification of classic T cell subsets and identification of novel cell types by single-cell RNA sequencing

2020 ◽  
Author(s):  
Xiangru Shen ◽  
Xuefei Wang ◽  
Shan Chen ◽  
Hongyi Liu ◽  
Ni Hong ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
T Cell Activation ◽  
Cell Activation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Types ◽  
T Cell Subsets ◽  
Single Cell Rna Sequencing

Abstract Single cell RNA sequencing (scRNA-seq) clusters cells using genome-wide gene expression profiles. The relationship between scRNA-seq Clustered-Populations (scCPops) and cell surface marker-defined classic T cell subsets is unclear. Here, we interrogated 6 bead-enriched T cell subsets with 62,235 single cell transcriptomes and re-grouped them into 9 scCPops. Bead-enriched CD4 Naïve, CD8 Naïve and CD4 memory were mainly clustered into their scCPop counterparts, while the other T cell subsets were clustered into multiple scCPops including unexpected mucosal-associated invariant T cell and natural killer T cell. Most interestingly, we discovered a new T cell type that highly expressed Interferon Signaling Associated Genes (ISAGs), namely IFNhi T. We further enriched IFNhi T for scRNA-seq analyses. IFNhi T cluster disappeared on tSNE after removing ISAGs, and IFNhi T cluster showed up by tSNE analyses of ISAGs alone, indicating ISAGs are the major contributor of IFNhi T cluster. BST2+ cells and BST2- cells showing different efficiencies of T cell activation indicates high ISAGs may contribute to quick immune responses.

scholarly journals Development of Nivolumab/Ipilimumab-Associated Autoimmune Nephritis during Steroid Therapy

2021 ◽  
pp. 270-274
Author(s):  
Ellen Gebauer ◽  
Wibke Bechtel-Walz ◽  
Christoph Schell ◽  
Michelle Erbel ◽  
Gerd Walz ◽  
...  
Keyword(s):  
Steroid Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Oral Steroid ◽  
High Dose ◽  
Immune Mediated

Immunotherapy using immune checkpoint inhibitors revolutionized therapies for a variety of malignancies. Nivolumab, an antibody blocking programmed cell death 1 protein, and ipilimumab that blocks cytotoxic T-lymphocyte-associated protein 4 effectively target tumor cells by disinhibiting the endogenous immune response. At the same time, unrestrained T-cell activation may trigger a range of immune-mediated side effects including kidney injury. Steroid therapy constitutes the mainstay of treatment of these adverse events, but dosage, route of administration, and approach to nivolumab re-exposure remain unclear. Here, we report the case of a 72-year-old male patient who developed severe nivolumab/ipilimumab-associated acute kidney injury while on oral steroid therapy for immune-mediated colitis. Acute interstitial nephritis was confirmed by renal biopsy. Administration of high-dose intravenous steroid doses was required to revert declining renal function.

scholarly journals Allogeneic T Cells Utilize Glycolysis As the Predominant Metabolic Pathway to Induce Acute Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2419-2419
Author(s):  
Hung Nguyen ◽  
Kelley MK Haarberg ◽  
Yongxia Wu ◽  
Jianing Fu ◽  
Jessica Lauren Heinrichs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Metabolic Process ◽  
Naive T Cells ◽  
Graft Versus Host ◽  
Naïve T Cells

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapy for hematologic malignancies through T cell-mediated graft-versus-leukemia (GVL) effects, but allogeneic T cells often lead to severe graft-versus-host disease (GVHD). Cell metabolism plays pivotal roles in T-cell activation, differentiation, and function. However, understanding of T cell-metabolism is still superficial, and even less is known how metabolism regulates T-cell response to alloantigens and GVHD induction after allo-HCT. In this study, using a high-throughput liquid-and gas-chromatography-based metabolic approach, we compared the metabolic process of allogeneic versus syngeneic T cells at day 4 (early preclinical stage), day 7 (preclinical stage), and day 14 (clinical stage) post bone marrow transplantation (BMT), with naïve T cells as additional controls. Over 180 metabolites were identified and quantified. T cells after being transferred into pre-conditioned recipients were undergoing metabolic reprogramming reflected by attenuated levels of metabolites involving anabolic pathways of lipids, amino acids, nucleotides and carbohydrates in allogeneic and syngeneic T cells compared to those in naïve T cells. In comparison with syngeneic T cells, allogeneic T cells exhibited increased oxidative stress, reflected by higher levels of eicosanoid, cyclooxygenase, and lipoxygenase-oxidized eicosanoids, and decreased levels of antioxidant compounds such as glutathione (GSH) and glutathione disulfide (GSSG). To obtain biomass for robust proliferation followed by alloantigen stimulation, allogeneic T cells further increased pentose phosphate and polyamine synthesis by day 7 post-BMT. We also observed that allogeneic T cells and syngeneic T cells expressed comparable levels of metabolites in fatty acid and glutamine oxidized in tricarboxylic acid (TCA) cycle, which was much lower than those of naïve T cells. Importantly, allogeneic T cells exhibited higher levels of metabolites in glycolysis as compared to syngeneic T cells regardless of time points. Consistently, using Seahorse approach, we also found that allogeneic T cells significantly increased aerobic glycolysis as compared to syngeneic T cells post-BMT, whereas oxidative phosphorylation was similar. Moreover, blocking glycolysis with 2-deoxyglucose remarkably inhibited donor T-cell proliferation, expansion and Th1 differentiation after allo-BMT. Thus, aerobic glycolysis rather than mitochondrial oxidative phosphorylation is the preferential metabolic process required for the optimal expansion and activation of allogeneic T cells. Given mechanistic target of rapamycin (mTOR) plays an essential role in controlling T-cell metabolism particularly in glycolysis, we hypothesized that targeting mTOR would prevent GVHD by inhibiting glycolytic metabolism. Using pharmacological and genetic approaches, we unequivocally demonstrated that mTOR, especially mTORC1, was essential for T-cell glycolytic activity and for GVHD induction. Mechanistically, mTORC1 promoted T-cell activation, expansion, Th1 differentiation, and migration into GVHD target organs, but inhibited the generation of induced T regulatory cells. In conclusion, the current work provides compelling evidence that allogeneic T cells utilize glycolysis as a predominant metabolic process after BMT. Furthermore, we validate glycolysis or its key regulator, such as mTORC1, to be a valid therapeutic target for the control of GVHD. Disclosures: No relevant conflicts of interest to declare.

Tim-1 promotes cisplatin nephrotoxicity

2011 ◽  
Vol 301 (5) ◽  
pp. F1098-F1104 ◽  
Author(s):  
Yuji Nozaki ◽  
David J. Nikolic-Paterson ◽  
Hideo Yagita ◽  
Hisaya Akiba ◽  
Stephen R. Holdsworth ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Kidney Injury ◽  
Mucin 1 ◽  
Antibody Treatment ◽  
Cisplatin Nephrotoxicity ◽  
Renal Tubular Cells ◽  
Kidney Injury Molecule 1

Nephrotoxicity is a frequent complication of cisplatin-based chemotherapy, in which T cells are known to promote acute kidney injury. In this study, we examined the role of T cell immunoglobulin mucin 1 (Tim-1) in cisplatin-induced acute kidney injury using an inhibitory anti-Tim-1 antibody. Tim-1 acts to modulate T cell responses, but it is also expressed by damaged proximal tubules in the kidney, where it is known as kidney injury molecule-1 (Kim-1). Anti-Tim-1 antibodies attenuated cisplatin nephrotocity, with less histologic damage, improved renal function, and fewer leukocytes infiltrating the kidney compared with control antibody-treated mice. Renal NF-κB activation and apoptosis were reduced, and proinflammatory renal cytokine and chemokine mRNA expression was decreased. Renal Kim-1 expression was reduced, consistent with the diminished kidney injury after anti-Tim-1 antibody treatment. Furthermore, anti-Tim-1 antibodies reduced early systemic CD4+ and CD8+ T cell activation, apoptosis, and cytokine production. To determine whether the protective actions of anti-Tim-1 antibodies were due to effects on renal tubular cells, cisplatin nephrotoxicity was studied in Rag1−/− mice. Anti-Tim-1 antibodies did not affect renal dysfunction or histologic damage in Rag1−/− mice, showing that the benefits of inhibiting Tim-1 come from T cell effects. As Tim-1 plays an important role in promoting cisplatin nephrotoxicity, inhibiting Tim-1 may be a therapeutic strategy to prevent cisplatin-induced acute kidney injury.

RHEOLOGY AND CELL ACTIVATION

1987 ◽  
Author(s):  
V L Mointire ◽  
A J Frangos ◽  
G B Rhee ◽  
G S Eskin ◽  
R E Hall
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Arachidonic Acid ◽  
Cell Activation ◽  
Acid Metabolism ◽  
Arachidonic Acid Metabolism ◽  
Cell Type ◽  
Induced Membrane ◽  
Lipoxygenase Products ◽  
Stimulation Of

The subject of this work is to examine the hypothesis that some sublytic levels of mechanical perturbation of cells can stimulate cell metabolism. As a marker metabolite, we have chosen arachidonic acid. Principal metabolites for platelets include the cyclooxygenase product thromboxane A2(TXA2) and the lipoxygenase product 12-hydroperoxy-eicosatetraenoic acid (12-HPETE). Polymorphonuclear leukocytes (PMNLs) initally produce principally 5-HPETE, somtimes leading to the formation leukotrienes, though many other metabolites of arachidonic acid have been isolated from activated neutrophils. Human umbilical vein endothelial cells utilize arachidonic acid to produce mainly prostaglandin I2(PGI2). All of these metabolites are biologically active and modulate cell function - sometimes in quite contrasting ways. We will show that levels of sublytic mechanical stress exposure can stimulate arachidonic acid metabolism in all three of the cell types mentioned above. The biological implications of this stress/metabolism coupling may be quite far reaching.Human platelets, leukocytes and endothelial cells all appear to be sensitive to mechanical stress induced activation of arachidonic acid metabolism. Sheared PRP exhibited greatly increased synthesis of 12-HETE and surprisingly little thromboxane B2 production. This indicates that shear stress stimulation of platelets may produce quite different arachidonic acid metabolism than that seen with many direct chemical stimuli, such as thrombin or collagen.Our data demonstrate that a substance derived from shear induced platelet activation may activate the C-5 lipoxygenase of human PMNL under stress, leading to the production of LTB4. We hypothesize that this substance maybe 12-HPETE. LTB4 is known to be a very potent chemotactic factor and to induce PMNL aggregation and degranulation. Our studies provide further evidence that lipoxygenase products of one cell type can modulate production of lipoxygenase products in a second cell type, and that shear stress can initiate cell activation. This kind of coupling could have far reaching implications in terms of our understanding of cell/cell interaction in flowing systems, such as acute inflammation, artificial organ implantation and tumor metastasis.The data on PGI2 production by endothelial cells demonstrate that physiological levels of shear stress can dramatically increase arachidonic acid metabolism. Step increases in shear stress lead to a burst in production of PGI2 which decayed to a steady state value in several minutes. This longer term stimulation of prostacyclin production rate increased linearly with shear stress over the range of 0-24 dynes/cm2. In addition, pulsatile flow of physiological frequency and amplitude caused approximately 2.4 times the PGI2 production rate as steady flow with the same mean stress. Although only PGI2 was measured, it is likely that other arachidonic acid metabolites of endothelial cells are also affected by shear stress.The ability of cells to respond to external stimuli involves the transduction of a signal across the plasma membrane. One such external stimulus appears to be fluid shear stress. Steady shear flow induces cell rotation in suspended cells, leading to a periodic membrane loading, with the peak stress proportional to the bulk shear stress. On anchorage-dependent cells, such as endothelial cells, steady shear stress may act by amplifying the natural thermal or Brownian fluttering or rippling of the membrane. There are several possible mechanisms by which shear stress induced membrane perturbation could mimic a hormone/receptor interaction, leading to increased intracellular metabolism. Shear stress may induce increased phospholipase C activity, caused by translocation of the enzyme, increased substrate (arachidonic acid) pool availability to phospholipase C (particularly from that stored in phosphoinositols) due to shear-induced membrane movements or changes in membrane fluidity, direct activation of calcium - activated phospholipase A2 by increased membrane calcium ion permeability, or most probably by a combination of these mechanisms.

IMMU-02. GENOMIC AND TRANSCRIPTOMIC CORRELATES OF IMMUNOTHERAPY RESPONSE WITHIN THE TUMOR MICROENVIRONMENT OF LEPTOMENINGEAL METASTASES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi92-vi92
Author(s):  
Christopher Alvarez-Breckenridge ◽  
Sanjay Prakadan ◽  
Samuel Markson ◽  
Albert Kim ◽  
Naema Nayyar ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
T Cell Activation ◽  
Antigen Processing ◽  
Cell Activation ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Leptomeningeal Disease ◽  
Ifn Gamma ◽  
Molecular Features

Abstract Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials utilizing either Pembrolizumab alone or the combination of Ipilimumab and Nivolumab. We investigated the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We isolated and sequenced 34,742 cells from both the malignant and immune compartment within CSF. Amongst the 19 patients included in the cohort, there were 13 pre-treatment and 24 post-treatment samples, and 9 patients were sampled across multiple timepoints. We detected dynamic changes in immune cell recruitment into the CSF and activation within 30 days of ICI, including increased effector T cell activation and IFN-gamma response pathways within T cells. Moreover, the overall level of IFN-gamma response and antigen processing within 30 days of ICI in malignant cells correlated with survival past clinical trial primary endpoint. Lastly, we observed evidence of longitudinal outgrowth of distinct immunogenic clones over the course of ICI. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and provides unique insights into the compartmental and temporal variation during the course of ICI. Moreover, our findings demonstrate the clinical utility of cell- free and single-cell genomic measurements for LMD research.

scholarly journals CD69 is expressed on platelets and mediates platelet activation and aggregation.

1990 ◽  
Vol 172 (3) ◽  
pp. 701-707 ◽  
Author(s):  
R Testi ◽  
F Pulcinelli ◽  
L Frati ◽  
P P Gazzaniga ◽  
A Santoni
Keyword(s):  
Platelet Activation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Human Platelets ◽  
Arachidonic Acid Metabolism ◽  
Lymphoid Cells ◽  
General Role ◽  
Dose Dependent Fashion

CD69, a surface dimer so far considered an early activation antigen restricted to lymphocytes, was found constitutively expressed on human platelets. Biochemical analysis revealed that platelet CD69 appears on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a broad 55-65-kD band, in which three 55-, 60-, and 65-kD components were detectable when nonreduced, and as two 28- and 32-kD bands when reduced, corresponding to the two disulfide-linked chains of the dimer. It therefore closely resembles lymphoid CD69, although the resolution of the three bands under nonreducing conditions is not usually seen in lymphoid cells. Moreover, as CD69 expressed on activated lymphocytes and CD3bright thymocytes, both chains are constitutively phosphorylated. CD69 stimulation by anti-Leu-23 monoclonal antibodies induced platelet aggregation in a dose-dependent fashion. This effect was associated with Ca2+ influx and platelet degranulation, as revealed by adenosine triphosphate release. In addition, CD69 stimulation in platelets induced production of thromboxane B2 and PGE2, suggesting activation of arachidonic acid metabolism by cycloxygenase. As observed for CD69-mediated T cell activation, platelet activation through CD69 requires molecular crosslinking. These results suggest that CD69 may function as an activating molecule on platelets, as on lymphocytes, and point toward a more general role of this surface dimer in signal transduction.

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