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CRISPR/Cas9 engineering of a KIM-1 reporter human proximal tubule cell line.
Veach RA, Wilson MH
(2018) PLoS One 13: e0204487
MeSH Terms: Acute Kidney Injury, CRISPR-Cas Systems, Cell Line, Cisplatin, Gene Knock-In Techniques, Gene Targeting, Genes, Reporter, Genetic Engineering, Glucose, Green Fluorescent Proteins, Hepatitis A Virus Cellular Receptor 1, Homologous Recombination, Humans, Kidney Tubules, Proximal, Luciferases, Up-Regulation
Show Abstract · Added December 13, 2018
We used the CRISPR/Cas9 system to knock-in reporter transgenes at the kidney injury molecule-1 (KIM-1) locus and isolated human proximal tubule cell (HK-2) clones. PCR verified targeted knock-in of the luciferase and eGFP reporter at the KIM-1 locus. HK-2-KIM-1 reporter cells responded to various stimuli including hypoxia, cisplatin, and high glucose, indicative of upregulation of KIM-1 expression. We attempted using CRISPR/Cas9 to also engineer the KIM-1 reporter in telomerase-immortalized human RPTEC cells. However, these cells demonstrated an inability to undergo homologous recombination at the target locus. KIM-1-reporter human proximal tubular cells could be valuable tools in drug discovery for molecules inhibiting kidney injury. Additionally, our gene targeting strategy could be used in other cell lines to evaluate the biology of KIM-1 in vitro or in vivo.
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16 MeSH Terms
Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR-21, -200c, and -423.
Pavkovic M, Robinson-Cohen C, Chua AS, Nicoara O, Cárdenas-González M, Bijol V, Ramachandran K, Hampson L, Pirmohamed M, Antoine DJ, Frendl G, Himmelfarb J, Waikar SS, Vaidya VS
(2016) Toxicol Sci 152: 205-13
MeSH Terms: Acetaminophen, Acute Kidney Injury, Adult, Biomarkers, Case-Control Studies, Cells, Cultured, Cisplatin, Cross-Sectional Studies, Dose-Response Relationship, Drug, Drug Overdose, Epithelial Cells, Female, Hepatitis A Virus Cellular Receptor 1, Humans, Kidney Tubules, Proximal, Longitudinal Studies, Male, MicroRNAs, Middle Aged, Predictive Value of Tests, Time Factors, Urinalysis, Young Adult
Show Abstract · Added September 19, 2017
Drug-induced acute kidney injury (AKI) is often encountered in hospitalized patients. Although serum creatinine (SCr) is still routinely used for assessing AKI, it is known to be insensitive and nonspecific. Therefore, our objective was to evaluate kidney injury molecule 1 (KIM-1) in conjunction with microRNA (miR)-21, -200c, and -423 as urinary biomarkers for drug-induced AKI in humans. In a cross-sectional cohort of patients (n = 135) with acetaminophen (APAP) overdose, all 4 biomarkers were significantly (P < .004) higher not only in APAP-overdosed (OD) patients with AKI (based on SCr increase) but also in APAP-OD patients without clinical diagnosis of AKI compared with healthy volunteers. In a longitudinal cohort of patients with malignant mesothelioma receiving intraoperative cisplatin (Cp) therapy (n = 108) the 4 biomarkers increased significantly (P < .0014) over time after Cp administration, but could not be used to distinguish patients with or without AKI. Evidence for human proximal tubular epithelial cells (HPTECs) being the source of miRNAs in urine was obtained first, by in situ hybridization based confirmation of increase in miR-21 expression in the kidney sections of AKI patients and second, by increased levels of miR-21, -200c, and -423 in the medium of cultured HPTECs treated with Cp and 4-aminophenol (APAP degradation product). Target prediction analysis revealed 1102 mRNA targets of miR-21, -200c, and -423 that are associated with pathways perturbed in diverse pathological kidney conditions. In summary, we report noninvasive detection of AKI in humans by combining the sensitivity of KIM-1 along with mechanistic potentials of miR-21, -200c, and -423.
© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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23 MeSH Terms
KIM-1/TIM-1 in proximal tubular cell immune response.
Brooks CR, Bonventre JV
(2015) Oncotarget 6: 44059-60
MeSH Terms: Acute Kidney Injury, Animals, Apoptosis, Disease Models, Animal, Genotype, Hepatitis A Virus Cellular Receptor 1, Humans, Ischemia, Kidney Tubules, Proximal, Membrane Proteins, Mice, Transgenic, Phagocytosis, Phenotype, Signal Transduction
Added September 12, 2016
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14 MeSH Terms
KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation.
Brooks CR, Yeung MY, Brooks YS, Chen H, Ichimura T, Henderson JM, Bonventre JV
(2015) EMBO J 34: 2441-64
MeSH Terms: Antigen Presentation, Apoptosis, Autophagy-Related Protein 5, Autophagy-Related Protein-1 Homolog, CD4-Positive T-Lymphocytes, Cell Proliferation, HEK293 Cells, Hepatitis A Virus Cellular Receptor 1, Humans, Intracellular Signaling Peptides and Proteins, Lipoylation, Membrane Glycoproteins, Microtubule-Associated Proteins, Phagocytosis, Protein-Serine-Threonine Kinases, Reactive Oxygen Species, Receptors, Virus
Show Abstract · Added September 12, 2016
Phagocytosis of apoptotic cells by both professional and semi-professional phagocytes is required for resolution of organ damage and maintenance of immune tolerance. KIM-1/TIM-1 is a phosphatidylserine receptor that is expressed on epithelial cells and can transform the cells into phagocytes. Here, we demonstrate that KIM-1 phosphorylation and association with p85 results in encapsulation of phagosomes by lipidated LC3 in multi-membrane organelles. KIM-1-mediated phagocytosis is not associated with increased ROS production, and NOX inhibition does not block LC3 lipidation. Autophagy gene expression is required for efficient clearance of apoptotic cells and phagosome maturation. KIM-1-mediated phagocytosis leads to pro-tolerogenic antigen presentation, which suppresses CD4 T-cell proliferation and increases the percentage of regulatory T cells in an autophagy gene-dependent manner. Taken together, these data reveal a novel mechanism of epithelial biology linking phagocytosis, autophagy and antigen presentation to regulation of the inflammatory response.
© 2015 The Authors.
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17 MeSH Terms
KIM-1-mediated phagocytosis reduces acute injury to the kidney.
Yang L, Brooks CR, Xiao S, Sabbisetti V, Yeung MY, Hsiao LL, Ichimura T, Kuchroo V, Bonventre JV
(2015) J Clin Invest 125: 1620-36
MeSH Terms: Acute Kidney Injury, Animals, Apoptosis, Cisplatin, Cytokines, Epithelial Cells, Extracellular Matrix Proteins, Gene Expression Regulation, Hepatitis A Virus Cellular Receptor 1, Homeodomain Proteins, Immunity, Innate, Inflammation, Intercellular Signaling Peptides and Proteins, Kidney, Kidney Tubules, Proximal, LLC-PK1 Cells, Macrophage Activation, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Phagocytosis, Phosphatidylinositol 3-Kinases, Protein Structure, Tertiary, Radiation Chimera, Reperfusion Injury, Swine
Show Abstract · Added September 12, 2016
Kidney injury molecule 1 (KIM-1, also known as TIM-1) is markedly upregulated in the proximal tubule after injury and is maladaptive when chronically expressed. Here, we determined that early in the injury process, however, KIM-1 expression is antiinflammatory due to its mediation of phagocytic processes in tubule cells. Using various models of acute kidney injury (AKI) and mice expressing mutant forms of KIM-1, we demonstrated a mucin domain-dependent protective effect of epithelial KIM-1 expression that involves downregulation of innate immunity. Deletion of the mucin domain markedly impaired KIM-1-mediated phagocytic function, resulting in increased proinflammatory cytokine production, decreased antiinflammatory growth factor secretion by proximal epithelial cells, and a subsequent increase in tissue macrophages. Mice expressing KIM-1Δmucin had greater functional impairment, inflammatory responses, and mortality in response to ischemia- and cisplatin-induced AKI. Compared with primary renal proximal tubule cells isolated from KIM-1Δmucin mice, those from WT mice had reduced proinflammatory cytokine secretion and impaired macrophage activation. The antiinflammatory effect of KIM-1 expression was due to the interaction of KIM-1 with p85 and subsequent PI3K-dependent downmodulation of NF-κB. Hence, KIM-1-mediated epithelial cell phagocytosis of apoptotic cells protects the kidney after acute injury by downregulating innate immunity and inflammation.
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29 MeSH Terms
Furosemide Stress Test and Biomarkers for the Prediction of AKI Severity.
Koyner JL, Davison DL, Brasha-Mitchell E, Chalikonda DM, Arthur JM, Shaw AD, Tumlin JA, Trevino SA, Bennett MR, Kimmel PL, Seneff MG, Chawla LS
(2015) J Am Soc Nephrol 26: 2023-31
MeSH Terms: Acute Kidney Injury, Acute-Phase Proteins, Aged, Albuminuria, Biomarkers, Creatinine, Disease Progression, Diuretics, Female, Furosemide, Hepatitis A Virus Cellular Receptor 1, Humans, Insulin-Like Growth Factor Binding Proteins, Interleukin-18, Lipocalin-2, Lipocalins, Male, Membrane Glycoproteins, Middle Aged, Proto-Oncogene Proteins, Receptors, Virus, Severity of Illness Index, Sodium, Tissue Inhibitor of Metalloproteinase-2, Uromodulin
Show Abstract · Added October 20, 2015
Clinicians have access to limited tools that predict which patients with early AKI will progress to more severe stages. In early AKI, urine output after a furosemide stress test (FST), which involves intravenous administration of furosemide (1.0 or 1.5 mg/kg), can predict the development of stage 3 AKI. We measured several AKI biomarkers in our previously published cohort of 77 patients with early AKI who received an FST and evaluated the ability of FST urine output and biomarkers to predict the development of stage 3 AKI (n=25 [32.5%]), receipt of RRT (n=11 [14.2%]), or inpatient mortality (n=16 [20.7%]). With an area under the curve (AUC)±SEM of 0.87±0.09 (P<0.0001), 2-hour urine output after FST was significantly better than each urinary biomarker tested in predicting progression to stage 3 (P<0.05). FST urine output was the only biomarker to significantly predict RRT (0.86±0.08; P=0.001). Regardless of the end point, combining FST urine output with individual biomarkers using logistic regression did not significantly improve risk stratification (ΔAUC, P>0.10 for all). When FST urine output was assessed in patients with increased biomarker levels, the AUC for progression to stage 3 improved to 0.90±0.06 and the AUC for receipt of RRT improved to 0.91±0.08. Overall, in the setting of early AKI, FST urine output outperformed biochemical biomarkers for prediction of progressive AKI, need for RRT, and inpatient mortality. Using a FST in patients with increased biomarker levels improves risk stratification, although further research is needed.
Copyright © 2015 by the American Society of Nephrology.
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25 MeSH Terms
TIM-1 signaling is required for maintenance and induction of regulatory B cells.
Yeung MY, Ding Q, Brooks CR, Xiao S, Workman CJ, Vignali DA, Ueno T, Padera RF, Kuchroo VK, Najafian N, Rothstein DM
(2015) Am J Transplant 15: 942-53
MeSH Terms: Animals, B-Lymphocytes, Regulatory, Graft Survival, Hepatitis A Virus Cellular Receptor 1, Interleukin-10, Membrane Proteins, Mice, Mice, Inbred BALB C, Signal Transduction
Show Abstract · Added September 12, 2016
Apart from their role in humoral immunity, B cells can exhibit IL-10-dependent regulatory activity (Bregs). These regulatory subpopulations have been shown to inhibit inflammation and allograft rejection. However, our understanding of Bregs has been hampered by their rarity, lack of a specific marker, and poor insight into their induction and maintenance. We previously demonstrated that T cell immunoglobulin mucin domain-1 (TIM-1) identifies over 70% of IL-10-producing B cells, irrespective of other markers. We now show that TIM-1 is the primary receptor responsible for Breg induction by apoptotic cells (ACs). However, B cells that express a mutant form of TIM-1 lacking the mucin domain (TIM-1(Δmucin) ) exhibit decreased phosphatidylserine binding and are unable to produce IL-10 in response to ACs or by specific ligation with anti-TIM-1. TIM-1(Δmucin) mice also exhibit accelerated allograft rejection, which appears to be due in part to their defect in both baseline and induced IL-10(+) Bregs, since a single transfer of WT TIM-1(+) B cells can restore long-term graft survival. These data suggest that TIM-1 signaling plays a direct role in Breg maintenance and induction both under physiological conditions (in response to ACs) and in response to therapy through TIM-1 ligation. Moreover, they directly demonstrate that the mucin domain regulates TIM-1 signaling.
© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
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9 MeSH Terms
Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation.
Xiao S, Brooks CR, Sobel RA, Kuchroo VK
(2015) J Immunol 194: 1602-8
MeSH Terms: Animals, B-Lymphocytes, Regulatory, Encephalomyelitis, Autoimmune, Experimental, Flow Cytometry, Hepatitis A Virus Cellular Receptor 1, Inflammation, Interleukin-10, Lymphocyte Activation, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Real-Time Polymerase Chain Reaction, Self Tolerance
Show Abstract · Added September 12, 2016
T cell Ig and mucin domain (Tim)-1 identifies IL-10-producing regulatory B cells (Bregs). Mice on the C57BL/6 background harboring a loss-of-function Tim-1 mutant showed progressive loss of IL-10 production in B cells and with age developed severe multiorgan tissue inflammation. We demonstrate that Tim-1 expression and signaling in Bregs are required for optimal production of IL-10. B cells with Tim-1 defects have impaired IL-10 production but increased proinflammatory cytokine production, including IL-1 and IL-6. Tim-1-deficient B cells promote Th1 and Th17 responses but inhibit the generation of regulatory T cells (Foxp3(+) and IL-10-producing type 1 regulatory T cells) and enhance the severity of experimental autoimmune encephalomyelitis. Mechanistically, Tim-1 on Bregs is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production in Bregs. Treatment with ACs reduces the severity of experimental autoimmune encephalomyelitis in hosts with wild-type but not Tim-1-deficient Bregs. Collectively, these findings suggest that in addition to serving as a marker for identifying IL-10-producing Bregs, Tim-1 is also critical for maintaining self-tolerance by regulating IL-10 production in Bregs.
Copyright © 2015 by The American Association of Immunologists, Inc.
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14 MeSH Terms
Urinary L-FABP predicts poor outcomes in critically ill patients with early acute kidney injury.
Parr SK, Clark AJ, Bian A, Shintani AK, Wickersham NE, Ware LB, Ikizler TA, Siew ED
(2015) Kidney Int 87: 640-8
MeSH Terms: APACHE, Acute Kidney Injury, Acute-Phase Proteins, Aged, Area Under Curve, Biomarkers, Creatinine, Critical Illness, Disease Progression, Early Diagnosis, Fatty Acid-Binding Proteins, Female, Hepatitis A Virus Cellular Receptor 1, Humans, Interleukin-18, Lipocalin-2, Lipocalins, Male, Membrane Glycoproteins, Middle Aged, Predictive Value of Tests, Proto-Oncogene Proteins, ROC Curve, Receptors, Virus, Renal Dialysis
Show Abstract · Added September 29, 2014
Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.
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25 MeSH Terms
Evaluation of 32 urine biomarkers to predict the progression of acute kidney injury after cardiac surgery.
Arthur JM, Hill EG, Alge JL, Lewis EC, Neely BA, Janech MG, Tumlin JA, Chawla LS, Shaw AD, SAKInet Investigators
(2014) Kidney Int 85: 431-8
MeSH Terms: Acute Kidney Injury, Adult, Aged, Aged, 80 and over, Area Under Curve, Biomarkers, Cardiac Surgical Procedures, Disease Progression, Female, Hepatitis A Virus Cellular Receptor 1, Humans, Interleukin-18, Male, Membrane Glycoproteins, Middle Aged, Predictive Value of Tests, Prognosis, ROC Curve, Receptors, Virus, Risk Assessment, Risk Factors, Severity of Illness Index, Time Factors, United States, Urinalysis
Show Abstract · Added June 29, 2015
Biomarkers for acute kidney injury (AKI) have been used to predict the progression of AKI, but a systematic comparison of the prognostic ability of each biomarker alone or in combination has not been performed. In order to assess this, we measured the concentration of 32 candidate biomarkers in the urine of 95 patients with AKIN stage 1 after cardiac surgery. Urine markers were divided into eight groups based on the putative pathophysiological mechanism they reflect. We then compared the ability of the markers alone or in combination to predict the primary outcome of worsening AKI or death (23 patients) and the secondary outcome of AKIN stage 3 or death (13 patients). IL-18 was the best predictor of both outcomes (AUC of 0.74 and 0.89). L-FABP (AUC of 0.67 and 0.85), NGAL (AUC of 0.72 and 0.83), and KIM-1 (AUC of 0.73 and 0.81) were also good predictors. Correlation between most of the markers was generally related to their predictive ability, but KIM-1 had a relatively weak correlation with other markers. The combination of IL-18 and KIM-1 had a very good predictive value with an AUC of 0.93 to predict AKIN 3 or death. Thus, a combination of IL-18 and KIM-1 would result in improved identification of high-risk patients for enrollment in clinical trials.
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25 MeSH Terms