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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
MeSH Terms: Anemia, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Clinical Trials, Phase III as Topic, Disease Models, Animal, Enzyme Inhibitors, Forkhead Transcription Factors, Humans, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Kidney Diseases, Mice, Molecular Targeted Therapy, Mutation, Organ Size, Procollagen-Proline Dioxygenase, Renal Insufficiency, Stromal Cells
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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20 MeSH Terms
Label-free molecular imaging of the kidney.
Prentice BM, Caprioli RM, Vuiblet V
(2017) Kidney Int 92: 580-598
MeSH Terms: Humans, Kidney, Kidney Diseases, Molecular Imaging, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Spectrophotometry, Infrared, Spectrum Analysis, Raman, Vibration
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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8 MeSH Terms
NADPH oxidase 4 deficiency increases tubular cell death during acute ischemic reperfusion injury.
Nlandu-Khodo S, Dissard R, Hasler U, Schäfer M, Pircher H, Jansen-Durr P, Krause KH, Martin PY, de Seigneux S
(2016) Sci Rep 6: 38598
MeSH Terms: Animals, Apoptosis, Cell Death, Creatinine, Disease Models, Animal, Gene Expression, Gene Expression Regulation, Genetic Predisposition to Disease, Glutathione, Kelch-Like ECH-Associated Protein 1, Kidney Diseases, Kidney Tubules, Mice, Mice, Knockout, Mitochondria, NADPH Oxidase 4, NF-E2-Related Factor 2, Oxidation-Reduction, Proto-Oncogene Proteins c-bcl-2, Reperfusion Injury
Show Abstract · Added December 26, 2018
NADPH oxidase 4 (NOX4) is highly expressed in kidney proximal tubular cells. NOX4 constitutively produces hydrogen peroxide, which may regulate important pro-survival pathways. Renal ischemia reperfusion injury (IRI) is a classical model mimicking human ischemic acute tubular necrosis. We hypothesized that NOX4 plays a protective role in kidney IRI. In wild type (WT) animals subjected to IRI, NOX4 protein expression increased after 24 hours. NOX4 KO (knock-out) and WT littermates mice were subjected to IRI. NOX4 KO mice displayed decreased renal function and more severe tubular apoptosis, decreased Bcl-2 expression and higher histologic damage scores compared to WT. Activation of NRF2 was decreased in NOX4 KO mice in response to IRI. This was related to decreased KEAP1 oxidation leading to decreased NRF2 stabilization. This resulted in decreased glutathione levels. In vitro silencing of NOX4 in cells showed an enhanced propensity to apoptosis, with reduced expression of NRF2, glutathione content and Bcl-2 expression, similar to cells derived from NOX4 KO mice. Overexpression of a constitutively active form of NRF2 (caNRF2) in NOX4 depleted cells rescued most of this phenotype in cultured cells, implying that NRF2 regulation by ROS issued from NOX4 may play an important role in its anti-apoptotic property.
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MeSH Terms
The origins of urinary stone disease: upstream mineral formations initiate downstream Randall's plaque.
Hsi RS, Ramaswamy K, Ho SP, Stoller ML
(2017) BJU Int 119: 177-184
MeSH Terms: Calcinosis, Humans, Kidney Diseases, Kidney Medulla, Minerals, Urinary Calculi
Show Abstract · Added January 16, 2018
OBJECTIVES - To describe a new hypothesis for the initial events leading to urinary stones. A biomechanical perspective on Randall's plaque formation through form and function relationships is applied to functional units within the kidney, we have termed the 'medullo-papillary complex' - a dynamic relationship between intratubular and interstitial mineral aggregates.
METHODS - A complete MEDLINE search was performed to examine the existing literature on the anatomical and physiological relationships in the renal medulla and papilla. Sectioned human renal medulla with papilla from radical nephrectomy specimens were imaged using a high resolution micro X-ray computed tomography. The location, distribution, and density of mineral aggregates within the medullo-papillary complex were identified.
RESULTS - Mineral aggregates were seen proximally in all specimens within the outer medulla of the medullary complex and were intratubular. Distal interstitial mineralisation at the papillary tip corresponding to Randall's plaque was not seen until a threshold of proximal mineralisation was observed. Mineral density measurements suggest varied chemical compositions between the proximal intratubular (330 mg/cm ) and distal interstitial (270 mg/cm ) deposits. A review of the literature revealed distinct anatomical compartments and gradients across the medullo-papillary complex that supports the empirical observations that proximal mineralisation triggers distal Randall's plaque formation.
CONCLUSION - The early stone event is initiated by intratubular mineralisation of the renal medullary tissue leading to the interstitial mineralisation that is observed as Randall's plaque. We base this novel hypothesis on a multiscale biomechanics perspective involving form and function relationships, and empirical observations. Additional studies are needed to validate this hypothesis.
© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.
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6 MeSH Terms
CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli.
Itani HA, Xiao L, Saleh MA, Wu J, Pilkinton MA, Dale BL, Barbaro NR, Foss JD, Kirabo A, Montaniel KR, Norlander AE, Chen W, Sato R, Navar LG, Mallal SA, Madhur MS, Bernstein KE, Harrison DG
(2016) Circ Res 118: 1233-43
MeSH Terms: Animals, Blood Pressure, CD27 Ligand, Hypertension, Inflammation Mediators, Kidney Diseases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NG-Nitroarginine Methyl Ester, Sodium Chloride, Dietary, T-Lymphocytes
Show Abstract · Added April 25, 2016
RATIONALE - Accumulating evidence supports a role of adaptive immunity and particularly T cells in the pathogenesis of hypertension. Formation of memory T cells, which requires the costimulatory molecule CD70 on antigen-presenting cells, is a cardinal feature of adaptive immunity.
OBJECTIVE - To test the hypothesis that CD70 and immunologic memory contribute to the blood pressure elevation and renal dysfunction mediated by repeated hypertensive challenges.
METHODS AND RESULTS - We imposed repeated hypertensive challenges using either N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME)/high salt or repeated angiotensin II stimulation in mice. During these challenges effector memory T cells (T(EM)) accumulated in the kidney and bone marrow. In the L-NAME/high-salt model, memory T cells of the kidney were predominant sources of interferon-γ and interleukin-17A, known to contribute to hypertension. L-NAME/high salt increased macrophage and dendritic cell surface expression of CD70 by 3- to 5-fold. Mice lacking CD70 did not accumulate T(EM) cells and did not develop hypertension to either high salt or the second angiotensin II challenge and were protected against renal damage. Bone marrow-residing T(EM) cells proliferated and redistributed to the kidney in response to repeated salt feeding. Adoptively transferred T(EM) cells from hypertensive mice homed to the bone marrow and spleen and expanded on salt feeding of the recipient mice.
CONCLUSIONS - Our findings illustrate a previously undefined role of CD70 and long-lived T(EM) cells in the development of blood pressure elevation and end-organ damage that occur on delayed exposure to mild hypertensive stimuli. Interventions to prevent repeated hypertensive surges could attenuate formation of hypertension-specific T(EM) cells.
© 2016 American Heart Association, Inc.
1 Communities
3 Members
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13 MeSH Terms
NO clue to pathogenesis of aristolochic acid nephropathy.
Gewin L
(2016) Exp Physiol 101: 33
MeSH Terms: Aristolochic Acids, Humans, Kidney Diseases
Added January 29, 2016
1 Communities
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3 MeSH Terms
KIDNEY DISEASE GENETICS AND THE IMPORTANCE OF DIVERSITY IN PRECISION MEDICINE.
Cooke Bailey JN, Wilson S, Brown-Gentry K, Goodloe R, Crawford DC
(2016) Pac Symp Biocomput 21: 285-96
MeSH Terms: Adult, African Americans, Computational Biology, Cross-Sectional Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Variation, Health Status Disparities, Humans, Kidney Diseases, Male, Mexican Americans, Middle Aged, Nutrition Surveys, Polymorphism, Single Nucleotide, Precision Medicine, Quantitative Trait Loci, United States
Show Abstract · Added May 5, 2017
Kidney disease is a well-known health disparity in the United States where African Americans are affected at higher rates compared with other groups such as European Americans and Mexican Americans. Common genetic variants in the myosin, heavy chain 9, non-muscle (MYH9) gene were initially identified as associated with non-diabetic end-stage renal disease in African Americans, and it is now understood that these variants are in strong linkage disequilibrium with likely causal variants in neighboring APOL1. Subsequent genome-wide and candidate gene studies have suggested that MYH9 common variants among others are also associated with chronic kidney disease and quantitative measures of kidney function in various populations. In a precision medicine setting, it is important to consider genetic effects or genetic associations that differ across racial/ethnic groups in delivering data relevant to disease risk or individual-level patient assessment. Kidney disease and quantitative trait-associated genetic variants have yet to be systematically characterized in multiple racial/ethnic groups. Therefore, to further characterize the prevalence of these genetic variants and their association with kidney related traits, we have genotyped 10 kidney disease or quantitative trait-associated single nucleotide polymorphisms (SNPs) (rs2900976, rs10505955, rs10502868, rs1243400, rs9305354, rs12917707, rs17319721, rs2467853, rs2032487, and rs4821480) in 14,998 participants from the population-based cross-sectional National Health and Nutrition Examination Surveys (NHANES) III and 1999-2002 as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study. In this general adult population ascertained regardless of health status (6,293 non-Hispanic whites, 3,013 non-Hispanic blacks, and 3,542 Mexican Americans), we observed higher rates of chronic kidney disease among non-Hispanic blacks compared with the other groups as expected. We performed single SNP tests of association using linear regressions assuming an additive genetic model adjusted for age, sex, diastolic blood pressure, systolic blood pressure, and type 2 diabetes status for several outcomes including creatinine (urinary), creatinine (serum), albumin (urinary), eGFR, and albumin-to-urinary creatinine ratio (ACR). We also tested for associations between each SNP and chronic kidney disease and albuminuria using logistic regression. Surprisingly, none of the MYH9 variants tested was associated with kidney diseases or traits in non-Hispanic blacks (p>0.05), perhaps attributable to the clinical heterogeneity of kidney disease in this population. Several associations were observed in each racial/ethnic group at p<0.05, but none were consistently associated in the same direction in all three groups. The lack of significant and consistent associations is most likely due to power highlighting the importance of the availability of large, diverse populations for genetic association studies of complex diseases and traits to inform precision medicine efforts in diverse patient populations.
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19 MeSH Terms
Cell Receptor-Basement Membrane Interactions in Health and Disease: A Kidney-Centric View.
Borza CM, Chen X, Zent R, Pozzi A
(2015) Curr Top Membr 76: 231-53
MeSH Terms: Animals, Basement Membrane, Epithelial Cells, Humans, Kidney, Kidney Diseases, Protein Binding, Receptors, Cell Surface
Show Abstract · Added February 4, 2016
Cell-extracellular matrix (ECM) interactions are essential for tissue development, homeostasis, and response to injury. Basement membranes (BMs) are specialized ECMs that separate epithelial or endothelial cells from stromal components and interact with cells via cellular receptors, including integrins and discoidin domain receptors. Disruption of cell-BM interactions due to either injury or genetic defects in either the ECM components or cellular receptors often lead to irreversible tissue injury and loss of organ function. Animal models that lack specific BM components or receptors either globally or in selective tissues have been used to help with our understanding of the molecular mechanisms whereby cell-BM interactions regulate organ function in physiological and pathological conditions. We review recently published works on animal models that explore how cell-BM interactions regulate kidney homeostasis in both health and disease.
Copyright © 2015 Elsevier Inc. All rights reserved.
1 Communities
2 Members
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8 MeSH Terms
Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.
Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, Saad AF, Li MK, Hughes MR, Werff RV, Peters DT, Lu J, Baccei A, Siedlecki AM, Valerius MT, Musunuru K, McNagny KM, Steinman TI, Zhou J, Lerou PH, Bonventre JV
(2015) Nat Commun 6: 8715
MeSH Terms: Cell Differentiation, Clustered Regularly Interspaced Short Palindromic Repeats, Embryonic Stem Cells, Gene Knockout Techniques, Germ Layers, Humans, Kidney, Kidney Diseases, Models, Biological, Organoids, Pluripotent Stem Cells, Sialoglycoproteins
Show Abstract · Added September 12, 2016
Human-pluripotent-stem-cell-derived kidney cells (hPSC-KCs) have important potential for disease modelling and regeneration. Whether the hPSC-KCs can reconstitute tissue-specific phenotypes is currently unknown. Here we show that hPSC-KCs self-organize into kidney organoids that functionally recapitulate tissue-specific epithelial physiology, including disease phenotypes after genome editing. In three-dimensional cultures, epiblast-stage hPSCs form spheroids surrounding hollow, amniotic-like cavities. GSK3β inhibition differentiates spheroids into segmented, nephron-like kidney organoids containing cell populations with characteristics of proximal tubules, podocytes and endothelium. Tubules accumulate dextran and methotrexate transport cargoes, and express kidney injury molecule-1 after nephrotoxic chemical injury. CRISPR/Cas9 knockout of podocalyxin causes junctional organization defects in podocyte-like cells. Knockout of the polycystic kidney disease genes PKD1 or PKD2 induces cyst formation from kidney tubules. All of these functional phenotypes are distinct from effects in epiblast spheroids, indicating that they are tissue specific. Our findings establish a reproducible, versatile three-dimensional framework for human epithelial disease modelling and regenerative medicine applications.
1 Communities
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12 MeSH Terms
Management of Indeterminate Cystic Kidney Lesions: Review of Contrast-enhanced Ultrasound as a Diagnostic Tool.
Chang EH, Chong WK, Kasoji SK, Dayton PA, Rathmell WK
(2016) Urology 87: 1-10
MeSH Terms: Contrast Media, Diagnosis, Differential, Disease Management, Humans, Kidney Diseases, Cystic, Ultrasonography
Show Abstract · Added August 8, 2016
Indeterminate cystic kidney lesions found incidentally are an increasingly prevalent diagnostic challenge. Standard workup includes Bosniak classification with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). However, these tests are costly and not without risks. Contrast-enhanced ultrasound (CEUS) is a relatively new technique with lower risk of adverse events than iodine-containing contrast or gadolinium. In our review of the evidence for characterization of cystic kidney lesions with CEUS, CEUS displayed sensitivity (89%-100%) and negative predictive value (86%-100%) comparable to contrast-enhanced CT or MRI, with no decrease in specificity compared with CT and only a slight decrease compared with MRI.
Copyright © 2015 Elsevier Inc. All rights reserved.
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6 MeSH Terms