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1
Tang, Chi-wai Sydney. "The many facets of the renal proximal tubular epithelial cell in human." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31992468.
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Tang, Chi-wai Sydney, and 鄧智偉. "The many facets of the renal proximal tubular epithelial cell inhuman." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31992468.
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Chen, Titi. "Type 1 conventional dendritic cells in kidney disease." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/27814.
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Dendritic cells (DCs) are central orchestrators of the immune system, which regulate both innate and adaptive immune responses. They can be broadly categorized into plasmacytoid DCs (pDCs) and conventional DCs (cDCs). cDC1s are a major subset of conventional DCs and play an important role in kidney disease. In this study, I firstly examined cDC1s in human kidney disease through analysing frozen human kidney biopsy samples. Secondly, I investigated the mechanisms of effects of cDC1s in experimental kidney disease, namely Adriamycin nephropathy and anti-GBM disease. Lastly, I explored the therapeutic potential of targeting cDC1s by repurposing Flt3 inhibitor for treatment of kidney disease.
In the human study, I found that the number of cDC1s correlated with disease severity in acute tubular necrosis, number of crescents in pauci-immune glomerular nephritis, interstitial fibrosis in IgA nephropathy and lupus nephritis, as well as prognosis in IgA nephropathy. The number of CD8+ T cells also increased significantly in these conditions and cDC1 number correlated with CD8+ T cell number. These findings reflected a possible role of cDC1s in these conditions and their association with CD8+ T cells suggested a combined mechanism in keeping with the results in animal models.
In the animal experiments, I studied cDC1s in vitro and in vivo using wild type as well as transgenic XCR1-DTR mice. In both Adriamycin nephropathy and anti-GBM disease, I found the number of cDC1s increased significantly. Depletion of cDC1s attenuated kidney injury, suggesting their pathogenic role. The mechanisms underlying cDC1 mediated kidney injury was demonstrated to relate to their superior ability to activate CD8+ T cells.
Flt3 is a receptor tyrosine kinase which regulates the differentiation of DCs and a Flt3 inhibitor is currently being used in cancer treatment. I demonstrated that a Flt3 inhibitor can deplete cDC1s with relative specificity. The Flt3 inhibitor attenuated kidney injury in both Adriamycin nephropathy and anti-GBM disease. Therefore, repurposing Flt3 inhibitor could be a novel therapeutic strategy to treat kidney disease.
4
Mora, Cristina Fuente. "Isolation and characterization of a novel population of potential kidney stem cells from postnatal mouse kidney." Thesis, University of Liverpool, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.507193.
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Brunskill, Nigel John. "Binding and uptake of albumin by opossum kidney cells." Thesis, University of Leicester, 1997. http://hdl.handle.net/2381/29459.
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Assays of both fluid phase endocytosis and receptor mediated endocytosis have been developed in opossum kidney cells. The regulation of the endocytic pathway has been examined using a number of potential inhibitors. In particular, bacterial toxins have been employed to identify potential points of regulation of the pathway by GTP-binding proteins. The apical endocytic pathway in these cells has been examined morphologically using electron microscopy of gold-albumin.;Based on the results of the above experiments a rat cDNA encoding the G-protein subunit G13 has been subcloned into pcDNA3. This vector has been stably transfected into opossum kidney cells by the calcium phosphate method. Over-expressing transfects have been selected and screened by western blotting and immunocytochemistry. These stable transfects have been used to measure albumin endocytosis and the results compared to control transfects and wild type cells.;Two binding sites for albumin have been identified, each with a different affinity. Based on the lectin competition studies the receptors appear to be glycoproteins carrying O-linked sugars. Specificity experiments indicate that the receptors share many similar characteristics to the family of scavenger receptors. [125I]-albumin ligand blotting has revealed the presence of three specific albumin binding proteins.;Endocytosis has been visualised using electron microscopy, with gold- albumin being seen in multiple intracellular vesicular structures. These endocytic pathways can be regulated by GTP-binding protein modulating agents. Opossum kidney cells have been successfully transfected with the Gi3 protein subunit. These cells show enhanced uptake of albumin compared to controls.;Therefore the experiments described in the thesis document the characteristics of albumin binding to opossum kidney cells, identify the potential receptors involved, and explore the mechanism of regulation of the subsequent endocytic uptake of albumin by the cells.
6
Measures, H. R. "A study of desmosome formation in kidney epithelial cells." Thesis, University of Southampton, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.234435.
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Lim, Ai Ing, and 林艾盈. "Shedding of kidney injury molecule-1 by kidney proximal tubular epithelial cells: the role of matrixmetalloproteinase-3." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B49799745.
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Regardless of the original cause and etiology, the progression of kidney disease follows a final common pathway associated with tubulointerstitial injury, in which proximal tubular epithelial cells (PTEC) are instrumental. Kidney injury molecule-1 (KIM-1) is an emerging biomarker of kidney tubular damage. It is markedly expressed and released into urine in various animal models and human kidney diseases. This study aimed to explore the underlying mechanism regulating the release of KIM-1 by PTEC.
First, expression and release of KIM-1 by primary cultured human PTEC were examined. In quiescent PTEC, KIM-1 was detected at the plasma membrane and in the cytoplasm. A transwell system, in which PTEC were grown as monolayer on permeable membrane, was used to examine the polarized release of KIM-1. PTEC constitutively released KIM-1 from their apical surface, and the release was independent of gene expression or protein synthesis. The KIM-1 release process by PTEC was enhanced dose- and time-dependently by two important kidney injury mediators, human serum albumin (HSA) and tumor necrosis factor (TNF)-α, and was inhibited by the presence of broad-spectrum inhibitors of matrix metalloproteinases (MMP).
Second, the potential sheddases responsible for KIM-1 shedding were identified by quantitative polymerase chain reaction (PCR) array system, in which the gene expression of a panel of MMP members was screened. The gene expression of MMP-3, MMP-7 and MMP-9 was up-regulated by PTEC under HSA or TNF-α activation. Blockade experiments with synthetic MMP inhibitors or MMP gene knockdown by small interfering RNA transfection, revealed that the constitutive or accelerated KIM-1 shedding was mediated by MMP-3, but not MMP-7 or MMP-9. The role of MMP-3 in KIM-1 shedding was further defined by additional data showing the enhanced MMP-3 synthesis by HSA- or TNF-α-stimulated PTEC, and the up-regulated KIM-1 shedding by PTEC following exogenous MMP-3 treatment.
Third, the regulatory mechanism of MMP-3-mediated KIM-1 shedding was investigated. Treatment of PTEC with HSA or TNF-α up-regulated the reactive oxygen species (ROS) generation, and its kinetics ran parallel to the increase of KIM-1 shedding and MMP-3 synthesis. In addition, exogenous hydrogen peroxide dose-dependently induced KIM-1 shedding and MMP-3 synthesis, which were abolished by the presence of an oxidation inhibitor. These evidence suggest that ROS play an essential role in regulating the MMP-3-mediated KIM-1 shedding by PTEC.
Finally, a mouse model of acute kidney injury induced by renal ischemia and reperfusion (I/R) was established to translate the in vitro findings. Reduced kidney function and increased urinary KIM-1 level were observed in mice after renal I/R treatment. Strikingly, the expression of MMP-3 and KIM-1 in the I/R treated mice was most profound in the S3 segments of the proximal tubules, where is the most susceptible area to oxidative stress. Taken together, these in vivo data have further strengthened the distinct roles of ROS and MMP-3 in KIM-1 shedding during PTEC injury.
In conclusion, ROS generated by the injured PTEC activate MMP-3, which release the soluble KIM-1 through the ectodomain shedding process.published_or_final_version
Medicine
Master
Master of Philosophy
8
Sampangi, Sandeep. "Autologous human kidney proximal tubule epithelial cells (PTEC) modulate dendritic cell (DC), T cell and B cell responses." Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/82033/1/Sandeep_Sampangi_Thesis.pdf.
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This is a comprehensive study of human kidney proximal tubular epithelial cells (PTEC) which are known to respond to and mediate the pathological process of a range of kidney diseases. It identifies various molecules expressed by PTEC and how these molecules participate in down-regulating the inflammatory process, thereby highlighting the clinical potential of these molecules to treat various kidney diseases. In the disease state, PTEC gain the ability to regulate the immune cell responses present within the interstitium. This down-regulation is a complex interaction of contact dependent/independent mechanisms involving various immuno-regulatory molecules including PD-L1, sHLA-G and IDO. The overall outcome of this down-regulation is suppressed DC maturation, decreased number of antibody producing B cells and low T cell responses. These manifestations within a clinical setting are expected to dampen the ongoing inflammation, preventing the damage caused to the kidney tissue.
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Prodromidi, Evangelia. "Contribution of bone marrow-derived stem cells to kidney regeneration." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444168.
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Katsoulieris, Elias. "Oxidatives and Endoplasmic Reticulum Stress in Kidney Priximal Tubule Cells." Thesis, University of Brighton, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.506517.
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Nova, Lamperti Estefania. "The role of transitional B cells in kidney transplantation tolerance." Thesis, King's College London (University of London), 2014. https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-transitional-b-cells-in-kidney-transplantation-tolerance(53e3fda4-26d6-4cbb-8c03-e667bab85705).html.
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Previous studies aimed at identifying biomarkers of tolerance in kidney transplant patients have revealed an expansion of peripheral blood B cells and over- expression of B cell-related genes. In humans, Memory, Naïve and Transitional B cells are the main B cell subsets found in circulation, and it is has been shown that the Transitional subset, defined by its regulatory properties, is expanded in tolerant recipients compared to non-tolerant kidney transplant patients. However, the role this population plays in kidney transplantation tolerance remains unclear. Here, we report three different mechanisms to explain the contribution of B cells in transplantation tolerance. Kidney transplant patients were divided into five groups; tolerant, stable, monotherapy, patients who lost tolerance and chronic rejector. In addition, this study also included a group of age/gender-matched healthy volunteers. B cells from each group of patients were tested for antigen presentation, antibody production, cytokine production, and co-stimulatory function. B cells from tolerant patients produced higher levels of IL-10 and lower levels of TNF-α than B cells from chronic rejector after CD40 and CpG activation. Moreover, B lymphocytes from tolerant patients also exhibited a failure in the BCR signalling pathway, suggesting a certain degree of anergy or responsiveness by these cells. Donor- specific assays revealed that B cells from tolerant patients were inefficient to recognise donor-antigens, compared to B cells from chronic rejector. This impairment prevented the triggering of the Th1 response by recipient CD4+ T cells and donor-specific antibody production by Plasma cells. Finally, Transitional B cells were the lowest CD4+ T cell- activating cells, compared to Naïve and Memory B cells. This reduced CD4+ T cell activation was due to low cell viability, reduced CD86 expression and high IL-10 production. In conclusion, these data suggest that B cells from kidney tolerant recipients contributed to maintaining organ acceptance and graft survival by donor-specific and non-specific regulatory properties exhibited by all their subsets, especially Transitional B cells.
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Xie, Jianxun. "Involvement of transcription factors in cadmium-induced apoptosis and cell cycle arrest in rat kidney cells /." View online ; access limited to URI, 2005. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3206258.
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Zhou, Li. "The molecular mechanisms of aristolochic acid nephropathy." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43224349.
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Ganeva, Veronika Veskova. "Acquisition of renogenic competence in the early mouse embryo and embryonic stem cells." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5907.
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The acquisition of renogenic competence (the ability to give rise to kidney) during embryonic development is not yet fully understood. Clarifying the temporal and molecular aspects of this process is equally essential for understanding excretory system development and for devising methods for successful differentiation of embryonic stem cells (ESCs) to renal cells for disease modeling, toxicology screening and potential cell replacement therapies. In embryo development, the metanephric (permanent) kidney arises as a result of inductive interactions between two embryonic structures that arise in the intermediate mesoderm - the ureteric bud (UB, a diverticulum of the Wolffian duct) and the metanephric mesenchyme (MM). The UB develops into the collecting duct system and the MM undergoes an epithelial-to-mesenchymal transition to form the secretory units of the kidney - the nephrons. In this thesis, I used a tissue disaggregation-reaggregation method that allows the reconstruction of mouse organotypic kidney rudiments to place different embryonic cells in the environment of a developing kidney and assess their potential to integrate into kidney epithelia and differentiate to renal cells. First, the suitability of this method was evaluated and a quantitative assay for evaluating the numbers of test cells integrating in various renal compartments was developed. Second, the reaggregation method was used to characterise the renogenic potential of undifferentiated mouse ESCs, ESC-derived cells after Notch inhibition, and cells derived from the presumptive nephrogenic regions of embryos at various stages of development. ESCs are isolated from the inner cell mass of an embryo and have the potential to differentiate to any tissue of the body when injected into mouse blastocysts. Strategies have successfully been devised for ESC differentiation to many lineages, but very few studies reported any success with the differentiation of ESCs to a renal lineage. Undifferentiated ESCs showed a very good ability to form chimeric structures with developing kidney tubules (both nephrons and extending UBs). Nevertheless, the resulting structures were morphologically different from renal epithelia in most cases and integrated ESC-derived cells were not positive for several combinations of kidney markers. These results suggested that the influence of the niche was not sufficient for a successful ESC differentiation to renal cells. Treatment of ESC with an inhibitor of the Notch pathway to increase the proportion of mesodermal cells did not improve this outcome. On the basis of these results, it was speculated that the earliest lineage to which embryonic stem cells must be differentiated in order to become competent to make renal cells should first be identified. I addressed this by determining the developmental stage at which cells able to contribute to the formation of metanephric epithelia first appear in mouse embryo development. When mixed in embryonic kidney reaggregates labelled cells isolated from the nephrogenic regions of E9.5 embryos integrated into various renal compartments. These cells were seen in UBs, nephrons, glomeruli and the condensing mesenchyme. Marker expression studies showed that the exogenous E9.5 cells expressed an array of kidney markers - Pax2 in renal epithelia and the condensing mesenchyme, Wt1 in glomeruli and Six2 in the condensing mesenchyme. Furthermore, exogenous E9.5 cells also co-expressed Pax2/Wt1 in the condensing mesenchyme, Megalin/Ecadherin in the proximal tubule and Pax2/E-cadherin in renal epithelia. This provides evidence that challenges the existing model and suggests that some cells from the intermediate mesoderm at a stage where the metanephric blastema is yet formed are competent to contribute to kidney structures. Furthermore, experiments with E8.5 embryos showed that such a renocompetence could be acquired even before the specification of intermediate mesoderm. These findings contribute to our knowledge about kidney cell specification and provide valuable information to guide future attempts to develop an efficient method for deriving renal cells from ESCs. Furthermore, the reported ability of ESC-derived non-kidney cells to form chimeric structures with renal tubules provides a proof-of-principle that it might be possible to use exogenous types of cells for physiological support to injured kidney tubules, thus offering a possible novel approach for cell replacement therapies.
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Ataya, Fernández Michelle 1993. "Adaptive NKG2C+ NK cells and cytomegalovirus infection in kidney transplant recipients." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2021. http://hdl.handle.net/10803/671368.
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Cytomegalovirus (CMV) infection in kidney transplant recipients (KTR) is frequent and may reduce graft and patient survival. T lymphocytes are essential to control the virus, which promotes the adaptive differentiation of NK cells characterized by CD94/NKG2C receptor expression. NKG2C+ NK cells and T lymphocytes were analyzed in a cohort of CMV seropositive KTR. Pretransplant NKG2C+ NK cells were associated with reduced incidence of symptomatic infection, and appeared unrelated with CMV-specific T cells in a parallel study, indicating that they may contribute to contain infection progression. Moreover, NKG2C+ NK cell expansions of variable magnitude developed following posttransplant infection. The data suggested that they participate in restoring the long-term CMV control, though their relative role could not be appreciated due to the overlapping effects of the infection on the T cell compartment. Combined assessment of T and NKG2C+ NK cells might allow a more precise assessment of CMV infection in KTR.La infección por citomegalovirus (CMV) en el trasplante renal (TR) es frecuente, reduciendo la supervivencia de injerto y paciente. Los linfocitos T son esenciales para controlar el virus, que además promueve la diferenciación adaptativa de células NK que expresan el receptor CD94/NKG2C. Se analizaron las células NKG2C+ y los linfocitos T en una cohorte de receptores de TR CMV+. Las células NKG2C+ pre-trasplante se asociaron a una menor incidencia de infección sintomática, sin relación con los linfocitos T específicos para CMV, indicando que pueden contribuir a contener la infección. La detección en grado variable de expansiones de células NKG2C+ tras la infección post-trasplante apunta también a su participación el control del CMV, pero su papel relativo no se apreció al solaparse con cambios en los linfocitos T. El estudio conjunto de las células T y NK NKG2C+ puede contribuir a una valoración más precisa de la infección por CMV.
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Baines, Richard John. "Megalin cytoplasmic tail phosphorylation and function in kidney proximal tubular cells." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9513.
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Selfa, Aspiroz Idoia Lucía 1992. "Engineering human pluripotent stem cells to understand kidney development and disease." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2022. http://hdl.handle.net/10803/673462.
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During the last years, the development of procedures to direct the differentiation of human pluripotent stem cells (hPSCs) towards different renal cell types has resulted in the establishment of approaches focused on the generation of kidney organoids. In addition, the possibility to modify the genome of hPSCs using the novel CRISPR-Cas9 editing technology has provided an unprecedented opportunity to study the role of specific proteins during nephrogenesis and renal pathogenesis in the human context. In the light of these findings, the main aim of this thesis was to develop new organoid model systems to investigate early steps of human kidney development and disease. Towards this goal, we first genetically engineered hPSCs to introduce loss-of-function and patient-specific mutations in WT1 and PAX2 renal transcription factors. The resulting CRISPR/Cas9 engineered hPSC clonal cell lines were further differentiated towards the renal lineage by the development of new culture methods including two-dimension (2D) and three-dimension (3D) settings. These cell culture platforms have allowed to properly dissect the role of WT1 and PAX2 in early stages of renal differentiation in vitro. Collectively, our results showed that lack of WT1 and PAX2 resulted in kidney differentiation impairment as well as the acquisition of relevant kidney disease-related phenotypes. In addition, a WT1 hPSC reporter cell line was generated and validated as a valuable tool to isolate WT1-expressing cellular populations for further characterization.
Altogether, this work demonstrates that genetically engineered kidney organoids represent an unvaluable model system to dissect the role of the renal markers WT1 and PAX2 in human kidney development and disease in vitro.Durante los últimos años, el desarrollo de procedimientos para dirigir la diferenciación de células madre pluripotentes humanas (hPSCs) hacia diferentes tipos celulares renales ha resultado en el establecimiento de estrategias enfocadas en la generación de organoides de riñón. Además, la posibilidad de modificar el genoma de las hPSC utilizando la nueva tecnología de edición génica CRISPR-Cas9 ha brindado una oportunidad sin precedentes para estudiar el papel de proteínas específicas durante la nefrogénesis y la patogénesis renal en el contexto humano. En base a estos hallazgos, el objetivo principal de esta tesis fue desarrollar nuevos sistemas de modelos de organoides para investigar los primeros pasos del desarrollo y la enfermedad del riñón humano. Con este objetivo, primero modificamos genéticamente las hPSC para introducir mutaciones de pérdida de función y mutaciones específicas de pacientes en los factores de transcripción renal WT1 y PAX2. Las líneas celulares clonales de hPSC que resultaron de la modificación genética usando CRISPR / Cas9 se diferenciaron hacia el linaje renal mediante el desarrollo de nuevos métodos de cultivo que incluyen configuraciones de dos dimensiones (2D) y tres dimensiones (3D). Estas plataformas de cultivo celular han permitido diseccionar adecuadamente el papel de WT1 y PAX2 en las primeras etapas de la diferenciación renal in vitro. En conjunto, nuestros resultados mostraron que la falta de WT1 y PAX2 dio como resultado un deterioro de la diferenciación renal, así como la adquisición de fenotipos relevantes relacionados con enfermedades renales. Además, se generó una línea hPSC para reportar la expression de WT1 y se validó como una herramienta valiosa para aislar poblaciones celulares que expresan la proteína WT1 y caracterizarlas en profundidad posteriormente.
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Marshburn, Erica Siovhan. "Characterization of Choline Transport in Human Embryonic Kidney (HEK-293) Cells." Thesis, The University of Arizona, 2011. http://hdl.handle.net/10150/144567.
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Law, Becker M. P. "The functional characterisation of human innate lymphocytes in renal fibrosis and chronic kidney disease." Thesis, Queensland University of Technology, 2019. https://eprints.qut.edu.au/132513/1/Becker%20Meng-Po_Law_Thesis.pdf.
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This thesis by publication is a step forward in understanding the function of discrete immune cell populations in kidneys with chronic inflammation and fibrosis. We have successfully identified various human immune cells of the innate immune system as critical drivers of chronic kidney disease. The findings of this thesis sheds light on novel functions of innate immune cells and opens opportunities for the development of novel kidney therapies.
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Dairi, Ghida Saleh. "Transcriptome-based analysis of molecular pathways for clusterin functions in kidney cells." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58192.
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Background: Clusterin (CLU) is a chaperone-like protein. Our previous studies have demonstrated that CLU protects kidney from ischemia-reperfusion injury (IRI) and enhances renal repair after IRI; however, the molecular pathways for its functions in the kidney are not fully understood. This study was designed to investigate CLU-mediating pathways in kidney cells by using bioinformatics analysis.
Materials and Methods: An in vitro model of kidney tissue using CLU null renal tubular epithelial cells (TECs) was established for this research project. An immortalized CLU null TEC cell line was generated from a CLU knockout (KO) mouse, and was stably expressing pHEX6300 plasmid containg human CLU cDNA (TEC-CLUhCLU), so that this cell line constitutively expresses human CLU protein, whereas control cell line (TEC-CLU-/-) was generated from the same parental CLU null TEC cell line by expressing empty pHEX6300. Both TEC-CLUhCLU and TEC-CLU-/- cell lines were exposed to either normoxia or hypoxia (1% O2). Transcriptome profiling with a significant 2-fold change (FC) (FC ≥ 2, p ≤ 0.05) was performed using SurePrint G3 Mouse Gene Expression 8×60K microarray, and the signaling pathways was ranked by using Ingenuity pathway analysis (IPA).
Results: Here, we showed that compared to CLU null TEC-CLU-/- controls ectopic expression of human CLU in CLU null kidney cells (TEC-CLUhCLU) promoted cell growth but inhibited migration in normoxia, and enhanced cell survival in hypoxia. CLU affected expression of 3864 transcripts (1893 up-regulated) in normoxia and 3670 transcripts (1925 up-regulated) in hypoxia. CLU functions including cell proliferation, survival and adhesion in normoxia were associated mostly with AKT2 dependent PI3K/AKT, PTEN, VEGF and ERK/MAPK signaling and as well with GSK3B-mediated cell cycle progression. In addition to unfolded protein response (UPR) and/or endoplasmic reticulum (ER) stress, CLU-enhanced cell survival in hypoxia was also associated with Foxo3/PIK3CD/MAPK1-dependent PI3K/AKT, HIF-α, PTEN, VEGF and ERK/MAPK signaling. Conclusion: Our data showed that CLU functions in kidney cells were mediated in a cascade manner mainly by PI3K/AKT, PTEN, VEGF and ERK/MAPK signaling, and specifically by activation of UPR/ER stress in hypoxia, providing new insights into the protective role of CLU in the kidney.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
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Broadbelt, Nalini V. "Regulation of iNOS expression : in response to pressure in proximal tubule epithelial cells /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1619205731&sid=2&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Lee, Pearly S. N. "Single cell studies of calcium as second messenger in human granulosa-lutein and embryonic kidney 293 cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0019/NQ48652.pdf.
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Laestadius, Åsa. "Cellular mechanisms of interaction between uropathogenic Escherichia coli and renal epithelial cells /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-187-X.
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Wang, Yang. "Murine adriamycin-induced nephropathy : the roles of cell-mediated immunity and CD4+ T-lymphocytes." Thesis, The University of Sydney, 2000. https://hdl.handle.net/2123/27827.
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Assmus, Adrienne Madeleine. "mCCDcl1 cells exhibit a transitional phenotype : implications for collecting duct plasticity." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31429.
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The cortical collecting duct of the mammalian kidney plays a critical role in the regulation of body volume, sodium pH and osmolarity and is composed of two distinct cells types, principal cells and intercalated cells. Each cell type is detectable in the kidney by the localization of specific transport proteins such as Aqp2 and ENaC in principal cells and V-ATPase B1 and Cx30 in intercalated cells. mCCDcl1 cells have been widely used as a mouse principal cell line on the basis of their physiological characteristics. In this study, the mCCDcl1 parental cell line and three sub-lines cloned from isolated single cells (Ed1, Ed2, and Ed3) were grown on filters to assess their transepithelial resistance, transepithelial voltage, equivalent short circuit current and expression of the cell-specific markers Aqp2, ENaC, V-ATPaseB1 and Cx30. The parental mCCDcl1 cell line presented amiloride-sensitive electrogenic sodium transport indicative of principal cell function, however immunocytochemistry and RT-PCR showed that some cells expressed the intercalated cell-specific markers V-ATPase B1 and Cx30, including a subset of cells also positive for Aqp2 and ENaC. The three subclonal lines contained cells that were positive for both intercalated and principal cell-specific markers. The vertical transmission of both principal and intercalated cell characteristics via single cell cloning, reveals the plasticity of mCCDcl1 cells, and a direct lineage relationship between these two physiologically important cell types, and is consistent with mCCDcl1 cells being precursor cells. For observation of live mCCDcl1 in an environment closer to in vivo conditions, a model of collecting duct was designed and developed using 3D printing of porous polymers. mCCDcl1 were cultured successfully and demonstrated improved characteristics compared to classic culture such as improved lifespan, different morphology and increased protein expression, and retained their phenotypic plasticity.
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Zhou, Juan. "Oral administration of alloantigen prolongs kidney allograft survival by generating intragraft regulatory cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/NQ66663.pdf.
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Rota, Cinzia. "Effect of foetal and adult stem cells in acute and chronic kidney diseases." Thesis, Open University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.594841.
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Acute kidney injury (AKl) and chronic kidney disease (CKD) are serious illnesses associated to high mortality and unsatisfactory therapeutic treatments. In search for new therapies, it has become evident that stem cells could be a possible option for patients with AKI and CKD. The evidence of the reno protective effect of bone marrow-mesenchymal stem cells (BM-MSCs) in experimental model of AKl, prompted us to study the effect of stem cells isolated from sources that are more accessible as cord blood (CB) and amniotic fluid. Infusion of hCB-MSCs in inununodeficient mice with AKI ameliorated renal function and tubular structure, prolonging survival. Moreover, transplanted hCB-MSCs localized in peritubular areas, limiting oxidative stress and apoptosis. By virtue of stem cell capacity to produce growth factors, hCB-MSCs were able- to induce the pro-survival factor Akt in tubular cells and subsequently their proliferation. Using the well-established model of AKI in immunodeficient mice, we studied the pro-regenerative effect of amniotic fluid stem (hAFS) cells. Infusion of hAPS cells in cisplatin-mice improved renal function and limited tubular damage, although not to control level, and prolonged animal survival. These cells engrafted injured kidney predominantly in peri tubular region and through a paracrine mechanism are able to exert an anti-apoptotic effect, to activate AId and stimulate proliferation of tubular cells. We enhanced the therapeutic potential of hAFS cells by cell pretreatment with GDNF, which markedly ameliorated renal function and tubular injury by increasing stem cell homing to the tubulointerstitial compartnent. In AKI models, the renoprotective effect of BM-MSCs is well established, however the role of these stem cells in model of eKD is controversial and not demonstrated so far. Therefore, we tested the effect of BM-MSCs in a model of adriarnycin-induced nephropathy. Repeated infusions of BMMSCs limited podocyte loss, and normalized distribution of parietal epithelial cells along the Bowman's capsule, reducing glomerulosclerosis. Moreover, through the local release of growth factors as VEGF, BM-MSCs were able to provide a local pro-survival environment that limited glomerular inflanunation and microvascular rarefaction.
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Sargazi, Mansour. "Biochemical and cytological studies of metal-induced damage to kidney proximal tubular cells." Thesis, University of Liverpool, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272775.
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Pollard, Hilary. "Studies on the localisation of eukarayotic initiation factors in Xenopus kidney B3.2 cells." Thesis, University of Sussex, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250127.
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Ranghini, Egon Jacopo. "Evaluating the expression profile and developmental potential of mouse kidney-derived stem cells." Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539593.
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Kasahara, Tomoko. "A modular differentiation system maps multiple human kidney lineages from pluripotent stem cells." Kyoto University, 2020. http://hdl.handle.net/2433/259016.
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Ollerstam, Anna. "Macula Densa Derived Nitric Oxide and Kidney Function." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5293-0/.
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McGoldrick, Trevor A. "C-S lyase-mediated toxicity in primary cultures of proximal tubular cells." Thesis, University of Aberdeen, 2000. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU602010.
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Halogenated alkenes are a group of commercially important chemicals. For example tetrafluoroethylene is the monomer used for the production of poly- tetrafluoroethylene, hexachloro-1:3-butadiene is a by-product from the manufacture of chlorinated solvents and perchloroethylene is widely used as a dry cleaning agent. Due to possible exposure to haloalkenes and the nephrotoxicity observed in animal studies, concern has been expressed for the potential of these compounds to cause toxicity to man. Animal studies have shown that these compounds undergo inter-organ metabolism and are bioactivated by enzymes of glutathione processing. The metabolites are delivered to the kidney where they cause proximal tubular cell necrosis. This site-specific toxicity is due to accumulation of the metabolites via specific transport mechanisms and bioactivation via the enzyme C-S lyase present in high amounts in the proximal tubules. The aim of this research was to investigate the mechanisms of toxicity of haloalkene S'-conjugates in vitro using cultures of rat and human proximal tubular cells. This study demonstrates that human proximal tubular cells are sensitive to haloalkene. -conjugate toxicity, particularly DC VC. Human exposuredata has shown that workers exposed to trichloroethylene (Bimer et al, 1993) and perchloroethylene (Mutti et al, 1992) excrete nephrotoxic metabolites and markers of renal damage respectively. In the light of these findings and the toxicity of DCVC in HPT cells, exposure to halogenated alkenes should be controlled and those exposed monitored.
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Keller, Christopher Philip. "The role of polysaccharidases in acid wall loosening of epidermal tissue from young Phaseolus vulgaris L. hypocotyls." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/26425.
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The extension of frozen-thawed epidermal strips prepared from the first centimetre below the hypocotyl hook of six day old dark grown Phaseolus vulgaris seedlings while immersed in various buffers and under various tensions was characterized. This was done in an attempt to determine if the acid wall loosening phenomenon, which according to the Acid-growth theory (Taiz, 1984) is thought to mimic part of the auxin mechanism of action, is mediated by unspecified wall loosening enzymes.
Epidermal strips were found to be significantly loosened by media pH 6.0 to pH 2.6 (0.05M citric acid-O.lOM disodium phosphate) relative to pH 7.5. A minimum stress between 1.6 and 7.6 grams was required for the acid-extension of strips 4.5±0.5 mm wide. Regardless of tension, extension by tissues in an acid medium was largely transient For example, tissues tensioned by a 16.0 gram load reached a maximum extension rate of 6.18 ±1.37% of initial length per hour (L°/hr) between 4 and 6 minutes after immersion in pH 4.8. The rate was 1.29±0.17% L°/hr between 55 and 60 minutes and 1.05±0.14% L°/hr between 220 and 240 minutes. Total acid-extension over four hours was 4.24±0.57% L°. The extension response was found to be stable; newly harvested tissues whether frozen or not performed similarly to strips aged up to 15 days at -12°C before being extended. The performance of strips immersed in unbuffered solutions indicated that tissues were self-buffering at an acid pH probably because of the fixed carboxyls within the wall. The capacity for acid-extension by epidermal strips was lost in mature tissues harvested 4-5 cm below the hypocotyl hook.
Temperature coefficients from extension rates were determined at several pHs. The results were highly variable. The acid-extension of strips boiled 15 minutes in ethanol or extracted in 3M NaCl for 4 hours at 4°C or 6M LiCl for 8 hours was determined in several pHs. The impact of the treatments was largely a suppression of the initial burst of acceleration. Extension rates following the initial surge were relatively unaffected. Glycosidase activities in untreated, ethanol-boiled, or salt extracted strips were determined. β-glucosidase was found to be most active in untreated strips with lesser levels of β-galactosidase and
β-xylosidase and a trace of α-galactosidase being detected. Ethanol-boiling and LiCl-extraction removed or deactivated all four activities from the strips and NaCl-extraction lowered all four activities 70-80%. NaCl proved to have solubilized most of the missing β-glucosidase and β-galactosidase when the extraction solution was assayed following desalting and concentration. LiCl solubilized most of β-xylosidase. It was concluded that glycosidases and any other similarly soluble enzyme cannot be responsible for long term acid wall loosening in bean epidermis. If an enzyme is involved, it must be extremely stable and tightly bound to the wall. The acid-extension performance of frozen-thawed longitudinally halved hypocotyl sections in comparison to epidermal strips, as well as other evidence was considered support for another hypothesized mechanism of acid wall loosening, the displacement of calcium bridges.Science, Faculty of
Botany, Department of
Graduate
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McLaren, John. "Human renal proximal tubular cells, in suspension and primary culture, as in vitro models of drug-induced nephrotoxicity." Thesis, University of Aberdeen, 1992. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU545620.
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The kidney is the target for a wide variety of chemical agents, including heavy metals, haloalkenes, analgesics and antibiotics. The functional and metabolic characteristics of the proximal tubule (PT) predispose it as the primary site for xenobiotic damage. The aim of this study was to isolate and characterise human and rat PT cells in suspension and primary culture for use as defined models to investigate drug-induced PT cell damage in vitro . A second aim was to compare the response of human and rat systems to known nephrotoxins. Human and rat PT cells (90&'37 viable) were isolated from kidney cortex by collagenase digestion followed by isopycnic Percoll density centrifugation. This resulted in the formation of two distinct bands of cell at densities 1.040g/ml (A) and 1.060g/ml (B) for both preparations. Characterisation of human cells in terms of morphology, marker enzymes, retention of active transport systems and responsiveness to parathyroid hormone indicated that &'62 95&'37 of the cells in band B were proximal tubular. Each transport system demonstrated Michaelis-Menten kinetics; kinetic parameters suggested that a higher proportion of PT cells from the S1-S2 segment of the nephron were present in human isolates. Human isolated cells also contained levels of glutathione and cytochrome P450, in particular ethoxyresorufin-O-deethylase activity, a marker for the P4501A family, similar to the intact kidney. Both human and rat cells were successfully cultured in serum-supplemented medium (10&'37 v/v) with human cells reaching confluence by 3-4 days and rat by 5-6. Maximal attachment was seen when cells from both preparations were inoculated onto collagen coated plates with an additional layer of fibronectin. Only human cells were able to reach confluence on porous membranes and demonstated an enhanced morphology when compared to normal cultured cells. Cultured cells from both preparations retained an epithelial morphology and showed minimal secondary cell contamination as shown by light microscopy and in the case of human cultures additionally through immunohistochemical staining. Immunohistochemical staining also demonstrated that human cells in culture were depositing components of the extracellular matrix. The maintenance of PT cell function, throughout the time in culture, was shown following maintenance of active transport systems, in particular the glucose carrier system and on porous membranes the organic anion system. Only rat cells maintained the organic cation system in primary culture. In addition human cells maintained the preferential response to parathyroid hormone. Except for the transport of organic cations, the other carrier systems and responsiveness to hormones were evident at both sub-confluent and confluent stages of cell culture.
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Olteanu, Dragos S. "Dysregulated ENAC and NHE function in cilium-deficient renal collecting duct cell monolayers a model of polycystic kidney disease /." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/olteanu.pdf.
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Zhou, Li, and 周莉. "The molecular mechanisms of aristolochic acid nephropathy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43224349.
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Ford, Loretta. "Molecular characterisation of phosphate transporters of ovine kidney proximal tubule and parotid acinar cells." Thesis, University of Liverpool, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367125.
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Wan, Kah Fei. "Characterisation of phosphodiesterase inhibitory proteins (PDE#gamma#) signalling in human embryonic kidney 293 cells." Thesis, University of Strathclyde, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288596.
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Shukla, D. H. "Manipulation of the VHL/HIF pathway in mouse kidney epithelia and pancreatic β-cells." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1306810/.
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Biallelic inactivation of the von Hippel-Lindau tumour suppressor gene (VHL) underlies both, sporadic clear cell renal cell carcinoma (ccRCC) that arises as part of an inherited multi-cancer VHL syndrome. Pancreatic tumours also occur in VHL disease and are thought to be of neuroendocrine origin. The most extensively studied role of VHL is hypoxia-inducible-factor (HIF) regulation. The HIF pathway is known operates in all cell types examined to date and plays a central role in many physiological responses to oxygen concentration. This thesis investigates the role of the Vhlh tumour suppressor protein in the kidney and pancreatic β-cells of mice. Cell-specific inactivation of Vhlh in mice was obtained using the Cre/loxP system. Analysis from mice constitutively expressing an active form of the HIF-2α transgene (KsptmHIF2α) was also performed. Furthermore, I have also used a doxycycline controlled Cre transgene system to allow temporal control of Vhlh ablation in the kidney. The main results arising from this thesis are: Vhlh inactivation in the distal tubular segment of the nephron led to an increase in both HIF isoforms (HIF-1α and HIF-2α) accompanied with upregulation of downstream gene expression. Constitutive expression of HIF-2α in the distal tubular segment upregulated downstream gene expression but did not lead to cyst or tumour formation; interestingly, inactivating another tumour suppressor gene, fumarate hydratase (Fh1) in the mouse kidney, resulted in cyst formation accompanied by HIF activation. Taken together, these findings suggest that HIF is not solely responsible for cyst formation in the Fh1 knockout mice, as cysts were not seen with the Vhlh knockout mice. The other major finding arising from this thesis is that, intact Vhlh is necessary for glucosestimulated- insulin secretion. I show that this is mediated via HIF transactivation and involves a glucose transporter switch, from glucose transporter–2 (GLUT-2) to glucose transporter–1 (GLUT-1). In addition, I have found that the expression of microRNA is altered in a murine pancreatic β-cell line, MIN6 in response to hypoxia. Therefore, the work arising from this thesis provides significant insights into understanding how the VHL/HIF pathway can be used to identify early morphological alterations, leading to a more aggressive phenotype or tumourigenesis. This pathway also plays a crucial role in glucose homeostasis, and interference in this pathway causes defects in β-cell function and insulin secretion.
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Stefanska, Anna Maria. "An affiliation between vascular pericytes and renin producing cells in the human foetal kidney." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17952.
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Pericytes, progenitor cells embedded in the microvascular wall, are crucial for vascular homeostasis. Renin is the rate-limiting enzyme that regulates blood pressure and fluid/electrolyte balance. Previous work suggested the relationship between renin-expressing/ producing cells and pericytes, however human kidney pericytes have not been characterized in depth and the molecular switch controlling renin cell plasticity is not understood. Here, I describe a method of isolation of CD146+CD34-CD45-CD56- pericytes, putative progenitors for renin-producing cells, from the human foetal kidney and demonstrate their potential in vitro to express and produce renin. Co-staining of pericyte markers (CD146 and NG2) and renin showed coincidence in the juxtaglomerular region and along renal arterioles in the human foetal kidney. I have obtained primary cultures of renal pericytes from the developing human kidney that were purified via fluorescence-activated cell sorting. Primary cultures of renal pericytes exhibited tri-lineage mesodermal differentiation potential. Renin expression was triggered by cAMP induction (10μM forskolin and 100μM 3-isobutyl-1- methylxanthine [IBMX] and resulted in 64.3 fold increase of renin mRNA (p <0.01) and 41.5 fold increase in enzymatic activity of renin (p <0.05) over controls. Pericytes derived from non-renal tissues (placenta and foetal adrenal glands) also expressed renin in an inducible fashion. Renin positive cells following induction were confirmed to be CD146+/NG2+. Interestingly, alpha-smooth muscle actin expression was not always correlated with renin immunostaining. Wnt/β-catenin signalling plays a crucial role during kidney development and in disease, specifically; in pericyte modulation of the Wnt pathway has been shown to regulate cell differentiation. CHIR 99021, a specific inhibitor of glycogen synthase kinase 3, mimicking Wnt signalling, and C59, a potent Porcupine acyltransferase inhibitor that is required for Wnt biological activity, were tested in renin induction experiments. Preliminary data showed that renin expression was blocked by Wnt activation, whereas Wnt suppression increased renin mRNA levels above the level of stimulation achieved with cAMP inducers. These findings provide evidence that renin expression is an intrinsic feature of pericytes and can be regulated through the Wnt pathway.
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Hageman, John Robert. "A morphometric and immunological analysis of kidney flask cells from the frog Xenopus laevis /." The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487682558447011.
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Almehmadi, Mazen. "CD56+ T-cells in relation to cytomegalovirus in healthy subjects and kidney transplant patients." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2008213/.
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Human T cells expressing CD56 are capable of tumour cell lysis following activation with interleukin-2 but their role in viral immunity has been less well studied. The work described in this thesis aimed to investigate CD56+ T-cells in relation to cytomegalovirus infection in healthy subjects and kidney transplant patients (KTPs). Proportions of CD56+ T cells were found to be highly significantly increased in healthy cytomegalovirus-seropositive (CMV+) compared to cytomegalovirus-seronegative (CMV-) subjects (8.38% ± 0.33 versus 3.29%± 0.33; P < 0.0001). In donor CMV-/recipient CMV- (D-/R-)- KTPs levels of CD56+ T cells were 1.9% ±0.35 versus 5.42% ±1.01 in D+/R- patients and 5.11% ±0.69 in R+ patients (P 0.0247 and < 0.0001 respectively). CD56+ T cells in both healthy CMV+ subjects and KTPs expressed markers of effector memory-RA T-cells (TEMRA) while in healthy CMV- subjects and D-/R- KTPs the phenotype was predominantly that of naïve T-cells. Other surface markers, CD8, CD4, CD58, CD57, CD94 and NKG2C were expressed by a significantly higher proportion of CD56+ T-cells in healthy CMV+ than CMV- subjects. Functional studies showed levels of pro-inflammatory cytokines IFN-γ and TNF-α, as well as granzyme B and CD107a were significantly higher in CD56+ T-cells from CMV+ than CMV- subjects following stimulation with CMV antigens. This also resulted in higher levels of proliferation in CD56+ T-cells from CMV+ than CMV- subjects. Using class I HLA pentamers, it was found that CD56+ T-cells from CMV+ subjects contained similar proportions of antigen-specific CD8+ T cells to CD56- T cells in healthy donors of several different HLA types. A comprehensive gene expression profile by microarrays of CMV-stimulated sorted CD56+ T-cells was conducted which showed that expression of 106 genes involved in innate and adaptive immune responses was significantly changed, almost all being increased. Some of these changes were validated via RT-PCR and flow cytometry, the latter indicating higher ISG-15 protein expression in response to CMV stimulation in CMV+ than CMV- subjects. Overall, these differences may reflect the expansion and enhanced functional activity of CMV-specific CD56+ memory T cells. In view of the link between CD56 expression and T-cell cytotoxic function, this strongly implicates CD56+ T cells as being an important component of the cytotoxic T-cell response to CMV.
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Hovater, Michael. "Underlying purinergic signaling important for monocilium-dependent signaling in ductal epithelia : implications for polycystic kidney disease." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2006. http://www.mhsl.uab.edu/dt/2007m/hovater.pdf.
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Fouletier, Christine. "Angiotensin II receptor gene expression in freshly isolated and cultured rat proximal tubular cells." Thesis, University of Aberdeen, 2001. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU136917.
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The renin-angiotensin system (RAS) is a major physiological regulator of body fluid volume, electrolyte balance and blood pressure. The principal effector peptides for this system are the angiotensins, particularly angiotensin II (Ang II), whose biological cations are mediated by specific angiotensin receptors. The use of highly specific nonpeptide angiotensin antagonists has allowed identification and characterisation of two major Ang II receptor subtypes, designated AT1 and AT2. The aims of this thesis were to investigate AT1 and AT2 receptor expression at both mRNA and protein level in freshly isolated and primary cultures of rat proximal tubular (PT) cells, and to determine the effect of culture upon Ang II receptor subtype expression. The possible role of Ang II upon receptor expression was also investigated. This study demonstrated that only the AT1 receptor is expressed in freshly isolated rat PT cells, with no evidence for AT2 receptor expression. Although continuously present throughout the culture period, a significant decrease in AT1 receptor expression was observed with time. Conversely AT2 receptor expression was absent in freshly isolated cells but was observed after 24 hours in culture with expression then remaining stable throughout culture. Clearly Ang II receptor expression is not stable during culture. Primary cultures of rat PT cells exhibit a change in receptor expression similar to those observed in vivo following tissue damage and repair, with an increase in AT2 receptor expression possibly mediated by locally released Ang II. Initial studies however, involving incubation of rat PT cells with exogenous Ang II, have demonstrated no effect upon AT1 receptor mRNA expression.
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Miskovic, Dragana. "A characterization of BiP gene expression in Xenopus laevis embryos and A6 kidney epithelial cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0021/NQ38257.pdf.
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Cegama, Bernardo Ortega Ladron de. "Functional expression and membrane trafficking of Kâ†iâ†r1.1b in Madin-Darby Canine Kidney cells." Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312366.
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White, Rebecca Lucy. "The recruitment mechanisms and beneficial roles of haematopoietic stem cells in murine acute kidney injury." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/4788/.
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Haematopoietic stem cells (HSCs) can migrate to the injured kidney and aid in tissue repair, however clinical success remains poor and is partially attributed to limited HSC recruitment. This study determined the molecular mechanisms governing HSC recruitment to the ischaemia-reperfusion (IR) injured kidney, whether this recruitment could be enhanced and also any immuno-modulatory effects HSCs may be having on surrounding injured microvasculature. HSC adhesion was significantly enhanced to the IR injured kidney compared to sham; this recruitment was governed by CD49d/VCAM-1 and CD44/HA. KC or SDF-1α pre-treatment enhanced HSC adhesion to the IR kidney. KC and SDF-1α also increased CD44 and CD49d surface clusters on HSCs respectively, and therefore increased HSC adhesion to HA and VCAM-1. Following injection into IR injured mice, HSCs improved blood flow and kidney function in the injured kidney compared to sham. This may be related to inflammatory modulation, as neutrophil recruitment and number of platelet microthrombi were reduced following HSC administration. This is the first study to show that pre-treatment of HSCs increases their recruitment to the site of injury, and that recruitment of HSCs can reduce inflammatory cell infiltration following injury.
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Martins, Sandra Cristina Pinto. "Evaluation of circulating endothelial progenitor cells by multicolor flow cytometry in chronic kidney disease patients." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/16135.
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Mestrado em Biologia Molecular e CelularEndothelial dysfunction and impaired endothelial regenerative capacity play a key role in the pathogenesis of cardiovascular disease, which is one of the major causes of mortality in chronic kidney disease (CKD) patients. Circulating endothelial cells (CEC) may be an indicator of vascular damage, while circulating endothelial progenitor cells (EPC) may be a biomarker for vascular repair. However, the simultaneously evaluation of CEC and EPC circulating levels and its relation were not previously examined in CKD population. A blood sample (18ml) of healthy subjects (n=10), early CKD (n=10) and advanced CKD patients (n=10) was used for the isolation of early and late EPCs, CECs, and hematopoietic cells, identified by flow cytometry (BD FACSCanto™ II system) using a combination of fluorochrome-conjugated primary antibodies: CD31-PE, CD45-APC Cy7, CD34-FITC, CD117-PerCp Cy5.5, CD133-APC, CD146-Pacific Blue, and CD309-PECy7. Exclusion of dead cells was done according to a fixable viability dye staining. This eightcolor staining flow cytometry optimized protocol allowed us to accurate simultaneously identify EPCs, CECs and hematopoietic cells. In addition, it was also possible to distinguish the two subpopulations of EPCs, early and late EPCs subpopulation, by CD45intCD31+CD34+CD117-CD133+CD309-CD146- and CD45intCD31+CD34+CD117-CD133-CD309+CD146- multiple labeling, respectively. Moreover, the identification of CECs and hematopoietic cells was performed by CD45-CD31+CD34-/lowCD117-CD133-CD309-CD146+ and CD34+CD117+, respectively. The levels of CECs were non-significantly increased in early CKD (312.06 ± 91.34) and advanced CKD patients (191.43±49.86) in comparison with control group (103.23±24.13). By contrast, the levels of circulating early EPCs were significantly reduced in advanced CKD population (17.03±3.23) in comparison with early CKD (32.31±4.97), p=0.04 and control group (36.25 ± 6.16), p=0.03. In addition the levels of late EPCs were significantly reduced in both advanced (6.60±1.89), p=0.01, and early CKD groups (8.42±2.58), p=0.01 compared with control group (91.54±29.06). These results were accompanied by a dramatically reduction in the recruitment, differentiation and regenerative capacity indexes in CKD population. Taken together, these results suggest an imbalance in the process of endothelial repairment in CKD population, and further propose that the indexes of recruitment, differentiation and regenerative capacity of EPCs, may help to select the patients to benefit from guiding intervention strategies to improve cardiovascular health by inducing vascular protection.
A disfunção endotelial e as alterações nos processos de regeneração endotelial podem desempenhar um papel determinante na patogénese da doença cardiovascular, que é uma das principais causas de mortalidade na doença renal crónica (DRC). As células endoteliais circulantes (CEC) podem ser um indicador de dano vascular, enquanto que as células progenitoras endoteliais circulantes (CPEC) pode ser um biomarcador de reparação vascular. No entanto, a avaliação simultânea dos níveis de CECs e de CPECs e sua relação não foram previamente avaliados numa população de doentes renais crónicos. Amostras de sangue (18 mL) foram recolhidas a partir de indivíduos saudáveis (n = 10), e a partir de doentes renais crónicos em estadios precoces (n=10) e em estádios avançados (n=10), para se proceder ao isolamento de populações de CPECs imaturas e maduras, CECs e células hematopoiéticas. Estas populações de células foram identificadas por citometria de fluxo (sistema BD FACS Canto II) usando uma combinação de anticorpos primários conjugados com fluorocromos: CD31-PE, CD45-APC Cy7, CD34-FITC, CD117-PerCp Cy5.5, CD133-APC, CD309-PE Cy7 e CD146-Paciific blue. Para a exclusão das células mortas recorreu-se a um marcador de viabilidade (“fixable viability dye”). Este protocolo otimizado de citometria de fluxo de oito cores permitiu identificar simultaneamente e com precisão as subpopulações de CECs, CPECs e células hematopoiéticas. Além disso, também foi possível distinguir as duas subpopulações de CPECs, imaturas e maduras, por marcação múltipla CD45intCD31+ CD34+ CD117-CD133+ CD309-CD146- e CD45intCD31+ CD34+CD117- CD133-CD309+ CD146-, respetivamente. Adicionalmente, a identificação de CECs e células hematopoiéticas foi realizada por CD45-CD31+ CD34-/lowCD117- CD133-CD309- CD146+ e CD34+ CD117+, respetivamente. Os níveis de CECs foram mais elevados em pacientes em estadios precoces de DRC (312,1±91,3) e em estadios avançados (191,4±49,9) comparativamente com o grupo controlo (103,23±24,13), n.s. Para além disso, os níveis de CPECs imaturas foram significativamente diminuídos em estadios avançados de DRC (17,1±3,2) em comparação com estadios precoces (32,3±4,9), p=0,04, e com o grupo controlo (36,3±6,2), p=0,03. Os níveis de CPECs maduras foram significativamente reduzidos em estadios avançados de DRC (6,6±1,9), p=0,01 e em estadios precoces (8,4±2,6), p=0,01, em comparação com o grupo controlo (91,5±29,1). Estes resultados foram acompanhados por uma diminuição acentuada nos índices de capacidade de recrutamento, diferenciação e regeneração na população de doentes renais crónicos. Globalmente, estes resultados sugerem um desequilíbrio no processo de reparação endotelial na DRC, e sugerem ainda, que os índices de recrutamento, diferenciação e regeneração podem ajudar na seleção de pacientes que possam beneficiar de estratégias de intervenção para melhorar a saúde cardiovascular induzindo proteção vascular.
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Abou, Samra Elias. "Elucidation of the Role of NKR‐P1: CLR Recognition Systems in Intestinal & Renal Epithelial Cell Homeostasis and Immunity." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35747.
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Natural killer (NK) cells represent a crucial component of the innate immune system and are primarily regulated by the interactions of their activation and inhibitory receptors with ligands available on target cells. The genetically linked Ly49 and NKR-P1 family of receptors constitute two of the major regulatory receptor systems used by NK cells and have been shown to bind different ligands. Whereas the Ly49 receptors survey MHC-I ligands on target cells, the NKR-Pl receptor family members bind to various members of the C-type lectin-related (Clr) family. Interestingly, NKR-P1 and Clr haplotypes possess a stable genomic polymorphism across multiple mouse strains, suggesting that this inhibitory receptor:ligand relationship has an important role in the maintenance of host cellular cognate specificities. The NKR-P1 and Clr receptor-ligand pairs identified in mice include the NKR-P1B:Clr-b and the NKR-P1G:Clr-f interacting pairs. Previous RT-PCR and in situ RNA hybridization data generated by our laboratory determined that kidney tubular epithelium as well as the small and large intestinal epithelial cells specifically and highly expresses the Clr-f transcripts. Contrarily, the Clr-b transcripts were only detected on hematopoietic cells of various lymphoid organs and kidneys. Moreover, foregoing studies revealed that the loss of Clr-b following viral or chemical induced stress mediates NK cell killing of the target cell, suggesting a tissue-specific immune-surveillance mechanism in parallel with the global MHC-I-dependent missing-self model. However, the role of the NKR-P1B:Clr-b recognition-system have never been examined in the intestine. Additionally, the role of Clr-f in the kidney and intestines, where they are highly expressed, has not been investigated. For these reasons, I aimed in my thesis to provide a better understanding of the functional aspect of the NKR-P1B:Clr-b and NKR-P1G:Clr-f recognition systems in mediating gut mucosal and renal homeostasis, respectively.
First, in order to determine the role of NKR-P1B and Clrb receptor:ligand pair as a “missing-self” immunosurveillance system in the gut, I started by identifying the expression pattern of both the receptor and ligand on various intestinal cells. My results demonstrate that NK cells do not represent the major NKR-P1B-expressing cells in the gut lamina propria. Instead, ILC3 subsets constituted the predominant cell population expressing the receptor, whereas γδT cells composed a small fraction of NKR-P1B+ lymphocytes. In addition, the NKR-P1B expression on myeloid cells was exclusive to colon macrophages and DC subsets. Interestingly, the highest percentage of NKR-P1B+ immune cells was found in the gut, which suggests the dominant role of NKR-P1B in regulating immune functions at the level of intestinal mucosa. As expected, the expression of the NKR-P1B ligand, Clr-b, appeared on all innate immune cell types in the gut. Next, using oral infection models of Salmonela typhimurium and Citrobacter rodentium, I showed that NKR-P1B-deficient NK cells, ILC3 and γδ T cells are hyporesponsive compared to their WT counterparts. In particular, gut NKR-P1B-deficient NK cells and γδT cells secreted low levels of IFNγ cytokine while infected with S.typhimurium. Importantly, the decreased IFNγ secretion by NK and γδT cells was associated with an increased dissemination of the bacterium into the knockout spleens at day 5 post-infection. Likewise, I detected a significant decrease in IL-22 cytokine production by NKR-P1B-deficient ILC3 compared to their WT counterparts at both steady state and following C.rodentium infection.
Next, I address the potential role of Clr-f in the kidney. Renal tubular epithelial cells have been shown to express high levels of Clr-f transcripts. Epithelial cells constitute the major cellular component of kidney tubules and are well known to mediate metabolic waste excretion, reabsorption of essential molecules as well as other physiological functions, such as ions exchange and water retention. To determine the role of Clr-f in renal epithelial cells, I generated a Clr-f-deficient mouse with the help of two of my previous lab colleagues. Importantly, chemical analysis on urine and serum samples from knockout and WT littermates indicated that Clr-f-deficient kidneys display a decreased filtration capacity. In particular, higher creatinine levels were detected in the Clr-f deficient serum. In addition, Clr-f-deficient mice appeared to have a lower fractional excretion of sodium (FENa) in their urine filtrates in comparison to WT excreted urine. Blood pressure measurements on the same mice at 12 and 24 weeks of age revealed a hypotensive phenotype in the Clr-f-deficient mice. Furthermore, pathological assessment of Clr-f-deficient kidneys exhibited moderate and aggravated lesions of the tubular epithelium along with marked glomerular mesangiolysis. Lastly, flow cytometry analysis on isolated lymphocytes from Clr-f-deficient and WT mice demonstrated comparable immune infiltrates between the two mouse genotypes.
Altogether, our data shows that the absence of Clr-f results in the development of glomerular and tubular lesions in an immune-independent manner leading to an abnormal kidney function. Additionally, the disruption of NKR-P1B:Clr-b recognition system results in abnormal innate immune cell number and function in the mouse intestine. These novel findings sheds light on the important role of Clr-f in maintaining healthy kidney morphology and function, as well as the crucial role for NKR-P1B:Clr-b interactions in mediating intestinal homeostasis at steady and infected states.