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IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori.
Dixon BR, Radin JN, Piazuelo MB, Contreras DC, Algood HM
(2016) PLoS One 11: e0148514
MeSH Terms: Animals, Anti-Infective Agents, CD4-Positive T-Lymphocytes, Epithelial Cells, Epithelium, Gastritis, Gastrointestinal Tract, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation, Interleukin-17, Interleukin-8, Interleukins, Leukocyte L1 Antigen Complex, Lipocalins, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Real-Time Polymerase Chain Reaction, Stomach
Show Abstract · Added April 28, 2016
Helicobacter pylori colonization of the human stomach can lead to adverse clinical outcomes including gastritis, peptic ulcers, or gastric cancer. Current data suggest that in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. Specifically, CD4+ T cell responses impact the pathology elicited in response to H. pylori. Because gastritis is believed to be the initiating host response to more detrimental pathological outcomes, there has been a significant interest in pro-inflammatory T cell cytokines, including the cytokines produced by T helper 17 cells. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22. While these cytokines have been linked to inflammation, IL-17A and IL-22 are also associated with anti-microbial responses and control of bacterial colonization. The goal of this research was to determine the role of IL-22 in activation of antimicrobial responses in models of H. pylori infection using human gastric epithelial cell lines and the mouse model of H. pylori infection. Our data indicate that IL-17A and IL-22 work synergistically to induce antimicrobials and chemokines such as IL-8, components of calprotectin (CP), lipocalin (LCN) and some β-defensins in both human and primary mouse gastric epithelial cells (GEC) and gastroids. Moreover, IL-22 and IL-17A-activated GECs were capable of inhibiting growth of H. pylori in vitro. While antimicrobials were activated by IL-17A and IL-22 in vitro, using a mouse model of H. pylori infection, the data herein indicate that IL-22 deficiency alone does not render mice more susceptible to infection, change their antimicrobial gene transcription, or significantly change their inflammatory response.
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22 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
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
Global analysis reveals the complexity of the human glomerular extracellular matrix.
Lennon R, Byron A, Humphries JD, Randles MJ, Carisey A, Murphy S, Knight D, Brenchley PE, Zent R, Humphries MJ
(2014) J Am Soc Nephrol 25: 939-51
MeSH Terms: Adult, Collagen Type VI, Extracellular Matrix Proteins, Gene Ontology, Humans, Kidney Glomerulus, Lipocalins, Male, Mass Spectrometry, Middle Aged, Protein Interaction Maps, Proteome
Show Abstract · Added February 25, 2014
The glomerulus contains unique cellular and extracellular matrix (ECM) components, which are required for intact barrier function. Studies of the cellular components have helped to build understanding of glomerular disease; however, the full composition and regulation of glomerular ECM remains poorly understood. We used mass spectrometry-based proteomics of enriched ECM extracts for a global analysis of human glomerular ECM in vivo and identified a tissue-specific proteome of 144 structural and regulatory ECM proteins. This catalog includes all previously identified glomerular components plus many new and abundant components. Relative protein quantification showed a dominance of collagen IV, collagen I, and laminin isoforms in the glomerular ECM together with abundant collagen VI and TINAGL1. Protein network analysis enabled the creation of a glomerular ECM interactome, which revealed a core of highly connected structural components. More than one half of the glomerular ECM proteome was validated using colocalization studies and data from the Human Protein Atlas. This study yields the greatest number of ECM proteins relative to previous investigations of whole glomerular extracts, highlighting the importance of sample enrichment. It also shows that the composition of glomerular ECM is far more complex than previously appreciated and suggests that many more ECM components may contribute to glomerular development and disease processes. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD000456.
Copyright © 2014 by the American Society of Nephrology.
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12 MeSH Terms
Plasma neutrophil gelatinase-associated lipocalin in acute kidney injury superimposed on chronic kidney disease after cardiac surgery: a multicenter prospective study.
Doi K, Urata M, Katagiri D, Inamori M, Murata S, Hisagi M, Ono M, Matsubara T, Ishii T, Yahagi N, Nangaku M, Noiri E
(2013) Crit Care 17: R270
MeSH Terms: Acute Kidney Injury, Acute-Phase Proteins, Aged, Biomarkers, Cardiac Surgical Procedures, Comorbidity, Creatinine, Female, Humans, Kidney Failure, Chronic, Lipocalin-2, Lipocalins, Male, Middle Aged, Postoperative Complications, Prospective Studies, Proto-Oncogene Proteins, ROC Curve, Tokyo
Show Abstract · Added February 11, 2016
INTRODUCTION - Plasma neutrophil gelatinase-associated lipocalin (NGAL) is reportedly useful for post-cardiac surgery acute kidney injury (AKI). Although chronic kidney disease (CKD) is a strong risk factor for AKI development, no clinical evaluation of plasma NGAL has specifically examined AKI occurring in patients with CKD. This study evaluated plasma NGAL in AKI superimposed on CKD after cardiac surgery.
METHODS - This study prospectively evaluated 146 adult patients with scheduled cardiac surgery at 2 general hospitals. Plasma NGAL was measured before surgery, at ICU arrival after surgery (0 hours), and 2, 4, 12, 24, 36, and 60 hours after ICU arrival.
RESULTS - Based on the Kidney Disease Improving Global Outcomes (KDIGO) CKD guideline, 72 (49.3%) were diagnosed as having CKD. Of 146 patients, 53 (36.3%) developed AKI after surgery. Multiple logistic regression analysis revealed that preoperative plasma NGAL, estimated glomerular filtration rate (eGFR), and operation time are significantly associated with AKI occurrence after surgery. Plasma NGAL in AKI measured after surgery was significantly higher than in non-AKI irrespective of CKD complication. However, transient decrease of plasma NGAL at 0 to 4 hours was observed especially in AKI superimposed on CKD. Plasma NGAL peaked earlier than serum creatinine and at the same time in mild AKI and AKI superimposed on CKD with increased preoperative plasma NGAL (>300 ng/ml). Although AKI superimposed on CKD showed the highest plasma NGAL levels after surgery, plasma NGAL alone was insufficient to discriminate de novo AKI from CKD without AKI after surgery. Receiver operating characteristics analysis revealed different cutoff values of AKI for CKD and non-CKD patients.
CONCLUSIONS - Results show the distinct features of plasma NGAL in AKI superimposed on CKD after cardiac surgery: 1) increased preoperative plasma NGAL is an independent risk factor for post-cardiac surgery AKI; 2) plasma NGAL showed an earlier peak than serum creatinine did, indicating that plasma NGAL can predict the recovery of AKI earlier; 3) different cutoff values of post-operative plasma NGAL are necessary to detect AKI superimposed on CKD distinctly from de novo AKI. Further investigation is necessary to confirm these findings because this study examined a small number of patients.
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19 MeSH Terms
Nrf2 is essential for the expression of lipocalin-prostaglandin D synthase induced by prostaglandin D2.
Kim KH, Sadikot RT, Xiao L, Christman JW, Freeman ML, Chan JY, Oh YK, Blackwell TS, Joo M
(2013) Free Radic Biol Med 65: 1134-1142
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Cell Line, Cyclooxygenase 2, Intramolecular Oxidoreductases, Lipocalins, Lipopolysaccharides, Lung, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2, Neutrophil Infiltration, Neutrophils, Pneumonia, Promoter Regions, Genetic, Prostaglandin D2, Protein Binding, RNA Interference, RNA, Small Interfering, Sequence Analysis, DNA, Toll-Like Receptor 4
Show Abstract · Added March 7, 2014
Nrf2 is a transcription factor that protects against inflammatory diseases, but the underlying mechanism of this effect remains unclear. Here, we report that Nrf2 uses lipocalin-prostaglandin D synthase (L-PGDS) as a mechanism for suppressing inflammation. Exogenously added prostaglandin D2 (PGD2) induced L-PGDS expression in bone-marrow-derived macrophages (BMDMs), suggesting a positive feedback loop between L-PGDS expression and PGD2. Unlike lipopolysaccharide (LPS)-induced L-PGDS expression, PGD2-mediated expression was independent of MAPK, PU.1, or TLR4. Sequence analysis located a putative Nrf2 binding site in the murine L-PGDS promoter, to which Nrf2 bound when treated with PGD2. Chemical activation, or overexpression, of Nrf2 was sufficient to induce L-PGDS expression in macrophages, BMDMs, or lungs of Nrf2-knockout (KO) mice, but treatment with PGD2 failed to do so, suggesting a pivotal role for Nrf2 in the expression of L-PGDS. Consistent with this, expression of Nrf2 in the lungs of Nrf2-KO mice was sufficient to induce the expression of L-PGDS and to reduce neutrophilic lung inflammation elicited by LPS. Furthermore, expression of L-PGDS in mouse lungs decreased neutrophilic infiltration, ameliorating lung inflammation in mice. Together, our results show that Nrf2, activated by PGD2, induced L-PGDS expression, resulting in decreased inflammation. We suggest that the positive feedback induction of L-PGDS by PGD2 is part of the mechanism by which Nrf2 regulates inflammation.
© 2013 Elsevier Inc. All rights reserved.
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25 MeSH Terms
Albuminuria induces a proinflammatory and profibrotic response in cortical collecting ducts via the 24p3 receptor.
Dizin E, Hasler U, Nlandu-Khodo S, Fila M, Roth I, Ernandez T, Doucet A, Martin PY, Feraille E, de Seigneux S
(2013) Am J Physiol Renal Physiol 305: F1053-63
MeSH Terms: Acute-Phase Proteins, Albumins, Albuminuria, Animals, Cell Line, Endocytosis, Kidney Tubules, Collecting, Lipocalin-2, Lipocalins, Male, Mice, NF-kappa B, Nephritis, Nephrosclerosis, Oncogene Proteins, Rats, Rats, Wistar, Transforming Growth Factor beta1
Show Abstract · Added December 26, 2018
Albuminuria is strongly associated with progressive kidney tubulo-interstitial damage and chronic kidney disease (CKD) progression. In proteinuric nephropathies, albumin reabsorption by the proximal tubule is saturated and the distal nephron is exposed to high concentrations of luminal albumin that may produce adverse effects. Since proximal tubular cells exposed to albuminuria exhibit a proinflammatory and profibrotic response, we assessed the effect of albuminuria in the collecting duct (CD). With the use of kidney sections and isolated cortical CDs (CCDs) from puromycin-aminonucleoside-induced nephrotic rats (PAN rats) exhibiting proteinuria, immunofluorescence microscopy revealed internalized albumin in CD cells. In these proteinuric rats, increased expression levels of cytokines and profibrotic signaling markers were detected in isolated CCDs and bands of inflammatory fibrosis could be observed around CDs. Albumin endocytosis was confirmed by FITC-albumin uptake in cultured murine CCD (mCCDcl1) cells. Exposure of mCCDcl1 cells to albumin induced NF-κB activation as assessed by luciferase reporter gene assay, nuclear translocation of NF-κB p65 subunit, and increased NF-κB target gene expression. Moreover, albuminuria-like condition results in transforming growth factor-β1 (TGF-β1) overexpression and the upregulation of profibrotic signaling markers such as Snail or vimentin via an autocrine mechanism. In mCCDcl1 cells, neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin-2/24p3 receptor (24p3R) mediates albumin endocytosis as well as activation of NF-κB and TGF-β1 signaling pathways. Therefore, CD may play a key role in initiation and/or progression of inflammation and fibrosis in response to proteinuria.
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Distinct injury markers for the early detection and prognosis of incident acute kidney injury in critically ill adults with preserved kidney function.
Siew ED, Ware LB, Bian A, Shintani A, Eden SK, Wickersham N, Cripps B, Ikizler TA
(2013) Kidney Int 84: 786-94
MeSH Terms: Acute Kidney Injury, Acute-Phase Proteins, Adult, Area Under Curve, Biomarkers, Case-Control Studies, Critical Illness, Cystatin C, Fatty Acid-Binding Proteins, Female, Glomerular Filtration Rate, Humans, Kidney, Lipocalin-2, Lipocalins, Male, Middle Aged, Prevalence, Prognosis, Proto-Oncogene Proteins, ROC Curve, Regression Analysis, Risk Factors
Show Abstract · Added August 21, 2013
The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is hindered by heterogeneity of injury and the potentially confounding effects of prevalent AKI. Here we examined the ability of urine NGAL (NGAL), L-type fatty acid-binding protein (L-FABP), and cystatin C to predict AKI development, death, and dialysis in a nested case-control study of 380 critically ill adults with an eGFR over 60 ml/min per 1.73 m(2). One-hundred thirty AKI cases were identified following biomarker measurement and were compared with 250 controls without AKI. Areas under the receiver-operator characteristic curves (AUC-ROCs) for discriminating incident AKI from non-AKI were 0.58 (95% CI: 0.52-0.64), 0.59 (0.52-0.65), and 0.50 (0.48-0.57) for urine NGAL, L-FABP, and cystatin C, respectively. The combined AUC-ROC for NGAL and L-FABP was 0.59 (56-0.69). Both urine NGAL and L-FABP independently predicted AKI during multivariate regression; however, risk reclassification indices were mixed. Neither urine biomarker was independently associated with death or acute dialysis (NGAL hazard ratio 1.35 (95% CI: 0.93-1.96), L-FABP 1.15 (0.82-1.61)), although both independently predicted the need for acute dialysis alone (NGAL 3.44 (1.73-6.83), L-FABP 2.36 (1.30-4.25)). Thus, urine NGAL and L-FABP independently associated with the development of incident AKI and receipt of dialysis but exhibited poor discrimination for incident AKI using conventional definitions.
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23 MeSH Terms
New biomarker panel of plasma neutrophil gelatinase-associated lipocalin and endotoxin activity assay for detecting sepsis in acute kidney injury.
Katagiri D, Doi K, Matsubara T, Negishi K, Hamasaki Y, Nakamura K, Ishii T, Yahagi N, Noiri E
(2013) J Crit Care 28: 564-70
MeSH Terms: Acute Kidney Injury, Acute-Phase Proteins, Biomarkers, Endotoxemia, Female, Humans, Intensive Care Units, Lipocalins, Male, Middle Aged, Predictive Value of Tests, Sensitivity and Specificity, Sepsis
Show Abstract · Added February 11, 2016
PURPOSE - Septic acute kidney injury (AKI) shows an unacceptably high mortality rate. Detection of sepsis is important for the clinical management of AKI patients. This study was undertaken to evaluate 2 biomarkers of neutrophil gelatinase-associated lipocalin (NGAL) and endotoxin activity (EA) assay and their combination for detecting sepsis in AKI.
MATERIALS AND METHODS - Adult intensive care unit patients consisting of 40 non-AKI, 65 AKI without sepsis, 10 non-AKI with sepsis, and 24 septic AKI were examined in a cross-sectional manner. Plasma NGAL and EA values in whole blood were measured at recruitment. We evaluated whether combining 2 different biomarkers would improve the performance of each biomarker using receiver operating characteristic analysis.
RESULTS - Plasma NGAL was significantly higher in septic AKI patients than in the other AKI patients and non-AKI patients, whereas EA values were higher in septic patients than nonseptic patients irrespective of AKI complication. Combination of plasma NGAL and EA value increased the area under the curve of the receiver operating characteristic curve and showed better performance compared with a clinical model consisting of clinically available variables.
CONCLUSION - Combinations of plasma NGAL and EA, which are operating via different pathological pathways, significantly improved their detection performance in complicated conditions of septic AKI.
Copyright © 2013 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Mild elevation of urinary biomarkers in prerenal acute kidney injury.
Doi K, Katagiri D, Negishi K, Hasegawa S, Hamasaki Y, Fujita T, Matsubara T, Ishii T, Yahagi N, Sugaya T, Noiri E
(2012) Kidney Int 82: 1114-20
MeSH Terms: Acetylglucosaminidase, Acute Kidney Injury, Acute-Phase Proteins, Aged, Albuminuria, Animals, Biomarkers, Cisplatin, Disease Models, Animal, Fatty Acid-Binding Proteins, Female, Humans, Intensive Care Units, Interleukin-18, Lipocalin-2, Lipocalins, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Transgenic, Middle Aged, Oncogene Proteins, Prospective Studies, Proto-Oncogene Proteins, Reperfusion Injury, Up-Regulation
Show Abstract · Added February 11, 2016
Prerenal acute kidney injury (AKI) is thought to be a reversible loss of renal function without structural damage. Although prerenal and intrinsic AKI frequently coexist in clinical situations, serum creatinine and urine output provide no information to support their differentiation. Recently developed biomarkers reflect tubular epithelial injury; therefore, we evaluated urinary biomarker levels in an adult mixed intensive care unit (ICU) cohort of patients who had been clinically evaluated as having prerenal AKI. Urinary L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), N-acetyl-β-D-glucosaminidase (NAG), and albumin in patients with prerenal AKI showed modest but significantly higher concentrations than in patients with non-AKI. We also conducted a proof-of-concept experiment to measure urinary biomarker excretion in prerenal AKI caused by volume depletion. Compared with cisplatinum and ischemia-reperfusion models in mice, volume depletion in mice caused a modest secretion of L-FABP and NGAL into urine with more sensitive response of L-FABP than that of NGAL. Although no histological evidence of structural damage was identified by light microscopy, partial kidney hypoxia was found by pimonidazole incorporation in the volume depletion model. Thus, our study suggests that new AKI biomarkers can detect mild renal tubular damage in prerenal acute kidney injury.
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27 MeSH Terms