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Imaging mass spectrometry reveals direct albumin fragmentation within the diabetic kidney.
Grove KJ, Lareau NM, Voziyan PA, Zeng F, Harris RC, Hudson BG, Caprioli RM
(2018) Kidney Int :
Show Abstract · Added May 29, 2018
Albumin degradation in the renal tubules is impaired in diabetic nephropathy such that levels of the resulting albumin fragments increase with the degree of renal injury. However, the mechanism of albumin degradation is unknown. In particular, fragmentation of the endogenous native albumin has not been demonstrated in the kidney and the enzymes that may contribute to fragmentation have not been identified. To explore this we utilized matrix-assisted laser desorption/ionization imaging mass spectrometry for molecular profiling of specific renal regions without disturbing distinct tissue morphology. Changes in protein expression were measured in kidney sections of eNOSdb/db mice, a model of diabetic nephropathy, by high spatial resolution imaging allowing molecular localizations at the level of single glomeruli and tubules. Significant increases were found in the relative abundances of several albumin fragments in the kidney of the mice with diabetic nephropathy compared with control nondiabetic mice. The relative abundance of fragments detected correlated positively with the degree of nephropathy. Furthermore, specific albumin fragments accumulating in the lumen of diabetic renal tubules were identified and predicted the enzymatic action of cathepsin D based on cleavage specificity and in vitro digestions. Importantly, this was demonstrated directly in the renal tissue with the endogenous nonlabeled murine albumin. Thus, our results provide molecular insights into the mechanism of albumin degradation in diabetic nephropathy.
Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
1 Communities
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0 MeSH Terms
Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development.
Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O, Saifudeen Z, Haase VH
(2017) Kidney Int 92: 1370-1383
Show Abstract · Added November 21, 2017
Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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0 MeSH Terms
Kidney function is associated with an altered protein composition of high-density lipoprotein.
Rubinow KB, Henderson CM, Robinson-Cohen C, Himmelfarb J, de Boer IH, Vaisar T, Kestenbaum B, Hoofnagle AN
(2017) Kidney Int 92: 1526-1535
Show Abstract · Added September 19, 2017
Patients with chronic kidney disease (CKD) exhibit a myriad of metabolic derangements, including dyslipidemia characterized by low plasma concentrations of high-density lipoprotein (HDL)-associated cholesterol. However, the effects of kidney disease on HDL composition have not been comprehensively determined. Here we used a targeted mass spectrometric approach to quantify 38 proteins contained in the HDL particles within a CKD cohort of 509 participants with a broad range of estimated glomerular filtration rates (eGFRs) (CKD stages I-V, and a mean eGFR of 45.5 mL/min/1.73m). After adjusting for multiple testing, demographics, comorbidities, medications, and other characteristics, eGFR was significantly associated with differences in four HDL proteins. Compared to participants with an eGFR of 60 mL/min/1.73mor more, those with an eGFR under 15 mL/min/1.73mexhibited 1.89-fold higher retinol-binding protein 4 (95% confidence interval 1.34-2.67), 1.52-fold higher apolipoprotein C-III (1.25-1.84), 0.70-fold lower apolipoprotein L1 (0.55-0.92), and 0.64-fold lower vitronectin (0.48-0.85). Although the HDL apolipoprotein L1 was slightly lower among African Americans than among Caucasian individuals, the relationship to eGFR did not differ by race. After adjustment, no HDL-associated proteins associated with albuminuria. Thus, modest changes in the HDL proteome provide preliminary evidence for an association between HDL proteins and declining kidney function, but this needs to be replicated. Future analyses will determine if HDL proteomics is indeed a clinical predictor of declining kidney function or cardiovascular outcomes.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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0 MeSH Terms
Label-free molecular imaging of the kidney.
Prentice BM, Caprioli RM, Vuiblet V
(2017) Kidney Int 92: 580-598
Show Abstract · Added March 22, 2018
In this review, we will highlight technologies that enable scientists to study the molecular characteristics of tissues and/or cells without the need for antibodies or other labeling techniques. Specifically, we will focus on matrix-assisted laser desorption/ionization imaging mass spectrometry, infrared spectroscopy, and Raman spectroscopy.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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1 Members
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0 MeSH Terms
Progression of chronic kidney disease: too much cellular talk causes damage.
Gewin L, Zent R, Pozzi A
(2017) Kidney Int 91: 552-560
MeSH Terms: Animals, Cell Communication, Cytokines, Fibrosis, Humans, Kidney, Renal Insufficiency, Chronic, Signal Transduction
Show Abstract · Added October 30, 2016
Tubulointerstitial fibrosis, tubular atrophy, and peritubular capillary rarefaction are major hallmarks of chronic kidney disease. The tubulointerstitium consists of multiple cell components including tubular epithelial, mesenchymal (fibroblasts and pericytes), endothelial, and inflammatory cells. Crosstalk among these cell components is a key component in the pathogenesis of this complex disease. After severe or recurrent injury, the renal tubular epithelial cells undergo changes in structure and cell cycle that are accompanied by altered expression and production of cytokines. These cytokines contribute to the initiation of the fibrotic response by favoring activation of fibroblasts, recruitment of inflammatory cells, and loss of endothelial cells. This review focuses on how augmented growth factor and cytokine production induces epithelial crosstalk with cells in the interstitium to promote progressive tubulointerstitial fibrosis after renal injury.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
1 Communities
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1 Resources
8 MeSH Terms
IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury.
Zhang MZ, Wang X, Wang Y, Niu A, Wang S, Zou C, Harris RC
(2017) Kidney Int 91: 375-386
MeSH Terms: Acute Kidney Injury, Animals, Cell Plasticity, Dendritic Cells, Diphtheria Toxin, Disease Models, Animal, Fibrosis, Genotype, Heparin-binding EGF-like Growth Factor, Interleukin-13, Interleukin-4, Janus Kinase 3, Kidney, Macrophages, Male, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Knockout, Phenotype, Recovery of Function, Reperfusion Injury, STAT6 Transcription Factor, Signal Transduction, Time Factors
Show Abstract · Added April 26, 2017
Cytokines IL-4 and IL-13 play important roles in polarization of macrophages/dendritic cells to an M2 phenotype, which is important for recovery from acute kidney injury. Both IL-4 and IL-13 activate JAK3/STAT6 signaling. In mice with diphtheria toxin receptor expression in proximal tubules (selective injury model), a relatively selective JAK3 inhibitor, tofacitinib, led to more severe kidney injury, delayed recovery from acute kidney injury, increased inflammatory M1 phenotype markers and decreased reparative M2 phenotype markers of macrophages/dendritic cells, and development of more severe renal fibrosis after diphtheria toxin administration. Similarly, there was delayed recovery and increased tubulointerstitial fibrosis in these diphtheria toxin-treated mice following tamoxifen-induced deletion of both IL-4 and IL-13, with increased levels of M1 and decreased levels of M2 markers in the macrophages/dendritic cells. Furthermore, deletion of IL-4 and IL-13 led to a decrease of tissue reparative M2a phenotype markers but had no effect on anti-inflammatory M2c phenotype markers. Deletion of IL-4 and IL-13 also inhibited recovery from ischemia-reperfusion injury in association with increased M1 and decreased M2 markers and promoted subsequent tubulointerstitial fibrosis. Thus, IL-4 and IL-13 are required to effectively polarize macrophages/dendritic cells to an M2a phenotype and to promote recovery from acute kidney injury.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
1 Communities
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24 MeSH Terms
Different components of blood pressure are associated with increased risk of atherosclerotic cardiovascular disease versus heart failure in advanced chronic kidney disease.
Bansal N, McCulloch CE, Lin F, Robinson-Cohen C, Rahman M, Kusek JW, Anderson AH, Xie D, Townsend RR, Lora CM, Wright J, Go AS, Ojo A, Alper A, Lustigova E, Cuevas M, Kallem R, Hsu CY, CRIC Study Investigators
(2016) Kidney Int 90: 1348-1356
MeSH Terms: Aged, Atherosclerosis, Blood Pressure, Diastole, Female, Heart Failure, Humans, Male, Middle Aged, Renal Insufficiency, Chronic, Systole
Show Abstract · Added September 19, 2017
Blood pressure is a modifiable risk for cardiovascular disease (CVD). Among hemodialysis patients, there is a U-shaped association between blood pressure and risk of death. However, few studies have examined the association between blood pressure and CVD in patients with stage 4 and 5 chronic kidney disease. Here we studied 1795 Chronic Renal Insufficiency Cohort (CRIC) Study participants with estimated glomerular filtration rate <30 ml/min per 1.73 mand not on dialysis. The association of systolic (SBP), diastolic (DBP), and pulse pressure with the risk of physician-adjudicated atherosclerotic CVD (stroke, myocardial infarction, or peripheral arterial disease) and heart failure was tested using Cox regression adjusted for demographics, comorbidity and medications. There was a significant association with higher SBP (adjusted hazard ratio 2.04 [95% confidence interval: 1.46-2.84]) for SBP over 140 vs under 120 mmHg, higher DBP (2.52 [1.54-4.11]) for DBP >90 mm Hg versus <80 mm Hg and higher pulse pressure (2.67 [1.82-3.92]) for pulse pressure >68 mm Hg versus <51 mm Hg with atherosclerotic CVD. For heart failure, there was a significant association with higher pulse pressure only (1.42 [1.05-1.92]) for pulse pressure >68 mm Hg versus <51 mmHg, but not for SBP or DBP. Thus, among participants with stage 4 and 5 chronic kidney disease, there was an independent association between higher SBP, DBP, and pulse pressure with the risk of atherosclerotic CVD, whereas only higher pulse pressure was independently associated with a greater risk of heart failure. Further trials are needed to determine whether aggressive reduction of blood pressure decreases the risk of CVD events in patients with stage 4 and 5 chronic kidney disease.
Copyright © 2016 International Society of Nephrology. All rights reserved.
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1 Members
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11 MeSH Terms
Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH
(2016) Kidney Int 90: 1115-1122
MeSH Terms: Aged, Anemia, Double-Blind Method, Female, Glycine, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Male, Middle Aged, Outcome Assessment (Health Care), Picolinic Acids, Renal Insufficiency, Chronic
Show Abstract · Added September 22, 2016
Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms
Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury.
Laskowski J, Renner B, Le Quintrec M, Panzer S, Hannan JP, Ljubanovic D, Ruseva MM, Borza DB, Antonioli AH, Pickering MC, Holers VM, Thurman JM
(2016) Kidney Int 90: 109-22
MeSH Terms: Animals, Complement C3, Complement Factor H, Complement Pathway, Alternative, Glomerulonephritis, Kidney Glomerulus, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Receptors, Complement
Show Abstract · Added December 2, 2016
Mutations in the complement regulatory proteins are associated with several different diseases. Although these mutations cause dysregulated alternative pathway activation throughout the body, the kidneys are the most common site of injury. The susceptibility of the kidney to alternative pathway-mediated injury may be due to limited expression of complement regulatory proteins on several tissue surfaces within the kidney. To examine the roles of the complement regulatory proteins factor H and Crry in protecting distinct renal surfaces from alternative pathway mediated injury, we generated mice with targeted deletions of the genes for both proteins. Surprisingly, mice with combined genetic deletions of factor H and Crry developed significantly milder renal injury than mice deficient in only factor H. Deficiency of both factor H and Crry was associated with C3 deposition at multiple locations within the kidney, but glomerular C3 deposition was lower than that in factor H alone deficient mice. Thus, factor H and Crry are critical for regulating complement activation at distinct anatomic sites within the kidney. However, widespread activation of the alternative pathway reduces injury by depleting the pool of C3 available at any 1 location.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
1 Communities
1 Members
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12 MeSH Terms
Is hemodiafiltration ready for broader use?
Golper TA
(2015) Kidney Int 88: 940-2
MeSH Terms: Europe, Hemodiafiltration
Show Abstract · Added December 3, 2015
Hemodiafiltration is practiced throughout Europe and in a few additional countries but, because of regulatory restrictions, is not currently available in the United States. Hemodiafiltration removes uremic species more broadly than is achieved by diffusion dialysis, perhaps explaining its better outcome profile.
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2 MeSH Terms