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  1. Article ; Online: Ex vivo modeling of chemical synergy in prenatal kidney cystogenesis.

    Corina Anders / Nick Ashton / Parisa Ranjzad / Mark R Dilworth / Adrian S Woolf

    PLoS ONE, Vol 8, Iss 3, p e

    2013  Volume 57797

    Abstract: Cyclic adenosine monophosphate (cAMP) drives genetic polycystic kidney disease (PKD) cystogenesis. Yet within certain PKD families, striking differences in disease severity exist between affected individuals, and genomic and/or environmental modifying ... ...

    Abstract Cyclic adenosine monophosphate (cAMP) drives genetic polycystic kidney disease (PKD) cystogenesis. Yet within certain PKD families, striking differences in disease severity exist between affected individuals, and genomic and/or environmental modifying factors have been evoked to explain these observations. We hypothesized that PKD cystogenesis is accentuated by an aberrant fetal milieu, specifically by glucocorticoids. The extent and nature of cystogenesis was assessed in explanted wild-type mouse embryonic metanephroi, using 8-Br-cAMP as a chemical to mimic genetic PKD and the glucocorticoid dexamethasone as the environmental modulator. Cysts and glomeruli were quantified by an observer blinded to culture conditions, and tubules were phenotyped using specific markers. Dexamethasone or 8-Br-cAMP applied on their own produced cysts predominantly arising in proximal tubules and descending limbs of loops of Henle. When applied together, however, dexamethasone over a wide concentration range synergized with 8-Br-cAMP to generate a more severe, glomerulocystic, phenotype; we note that prominent glomerular cysts have been reported in autosomal dominant PKD fetal kidneys. Our data support the idea that an adverse antenatal environment exacerbates renal cystogenesis.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Experimental long-term diabetes mellitus alters the transcriptome and biomechanical properties of the rat urinary bladder

    Emad A. Hindi / Craig J. Williams / Leo A. H. Zeef / Filipa M. Lopes / Katie Newman / Martha M. M. Davey / Nigel W. Hodson / Emma N. Hilton / Jennifer L. Huang / Karen L. Price / Neil A. Roberts / David A. Long / Adrian S. Woolf / Natalie J. Gardiner

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 16

    Abstract: Abstract Diabetes mellitus (DM) is the leading cause of chronic kidney disease and diabetic nephropathy is widely studied. In contrast, the pathobiology of diabetic urinary bladder disease is less understood despite dysfunctional voiding being common in ... ...

    Abstract Abstract Diabetes mellitus (DM) is the leading cause of chronic kidney disease and diabetic nephropathy is widely studied. In contrast, the pathobiology of diabetic urinary bladder disease is less understood despite dysfunctional voiding being common in DM. We hypothesised that diabetic cystopathy has a characteristic molecular signature. We therefore studied bladders of hyperglycaemic and polyuric rats with streptozotocin (STZ)-induced DM. Sixteen weeks after induction of DM, as assessed by RNA arrays, wide-ranging changes of gene expression occurred in DM bladders over and above those induced in bladders of non-hyperglycaemic rats with sucrose-induced polyuria. The altered transcripts included those coding for extracellular matrix regulators and neural molecules. Changes in key genes deregulated in DM rat bladders were also detected in db/db mouse bladders. In DM rat bladders there was reduced birefringent collagen between detrusor muscle bundles, and atomic force microscopy showed a significant reduction in tissue stiffness; neither change was found in bladders of sucrose-treated rats. Thus, altered extracellular matrix with reduced tissue rigidity may contribute to voiding dysfunction in people with long-term DM. These results serve as an informative stepping stone towards understanding the complex pathobiology of diabetic cystopathy.
    Keywords Medicine ; R ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Generation of Functioning Nephrons by Implanting Human Pluripotent Stem Cell-Derived Kidney Progenitors

    Ioannis Bantounas / Parisa Ranjzad / Faris Tengku / Edina Silajdžić / Duncan Forster / Marie-Claude Asselin / Philip Lewis / Rachel Lennon / Antonius Plagge / Qi Wang / Adrian S. Woolf / Susan J. Kimber

    Stem Cell Reports, Vol 10, Iss 3, Pp 766-

    2018  Volume 779

    Abstract: Summary: Human pluripotent stem cells (hPSCs) hold great promise for understanding kidney development and disease. We reproducibly differentiated three genetically distinct wild-type hPSC lines to kidney precursors that underwent rudimentary ... ...

    Abstract Summary: Human pluripotent stem cells (hPSCs) hold great promise for understanding kidney development and disease. We reproducibly differentiated three genetically distinct wild-type hPSC lines to kidney precursors that underwent rudimentary morphogenesis in vitro. They expressed nephron and collecting duct lineage marker genes, several of which are mutated in human kidney disease. Lentiviral-transduced hPSCs expressing reporter genes differentiated similarly to controls in vitro. Kidney progenitors were subcutaneously implanted into immunodeficient mice. By 12 weeks, they formed organ-like masses detectable by bioluminescence imaging. Implants included perfused glomeruli containing human capillaries, podocytes with regions of mature basement membrane, and mesangial cells. After intravenous injection of fluorescent low-molecular-weight dextran, signal was detected in tubules, demonstrating uptake from glomerular filtrate. Thus, we have developed methods to trace hPSC-derived kidney precursors that formed functioning nephrons in vivo. These advances beyond in vitro culture are critical steps toward using hPSCs to model and treat kidney diseases. : Kimber and colleagues show that pluripotent stem cell-derived kidney progenitors implanted subcutaneously generate vascularized glomeruli including podocytes with slit diaphragms and mature glomerular basement membranes indicative of functioning glomeruli. Human cells contributed to the vasculature, and the glomeruli were able to filter low-molecular-weight dextran injected intravenously, which appeared in some tubules. Keywords: human embryonic stem cells, kidney, nephron, glomerulus, lentivirus, kidney progenitors, metanephric mesenchyme, ureteric epithelium, vascularization, cell therapy
    Keywords Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Spatiotemporal dynamics and heterogeneity of renal lymphatics in mammalian development and cystic kidney disease

    Daniyal J Jafree / Dale Moulding / Maria Kolatsi-Joannou / Nuria Perretta Tejedor / Karen L Price / Natalie J Milmoe / Claire L Walsh / Rosa Maria Correra / Paul JD Winyard / Peter C Harris / Christiana Ruhrberg / Simon Walker-Samuel / Paul R Riley / Adrian S Woolf / Peter J Scambler / David A Long

    eLife, Vol

    2019  Volume 8

    Abstract: Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three- ... ...

    Abstract Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three-dimensional imaging to characterize lymphatic vessel formation in the mammalian embryonic kidney at single-cell resolution. In mouse, we visually and quantitatively assessed the development of kidney lymphatic vessels, remodeling from a ring-like anastomosis under the nascent renal pelvis; a site of VEGF-C expression, to form a patent vascular plexus. We identified a heterogenous population of lymphatic endothelial cell clusters in mouse and human embryonic kidneys. Exogenous VEGF-C expanded the lymphatic population in explanted mouse embryonic kidneys. Finally, we characterized complex kidney lymphatic abnormalities in a genetic mouse model of polycystic kidney disease. Our study provides novel insights into the development of kidney lymphatic vasculature; a system which likely has fundamental roles in renal development, physiology and disease.
    Keywords kidney ; lymphatics ; vessels ; development ; kidney disease ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy

    Enrico Mingardo / Glenda Beaman / Philip Grote / Agneta Nordenskjöld / William Newman / Adrian S. Woolf / Markus Eckstein / Alina C. Hilger / Gabriel C. Dworschak / Wolfgang Rösch / Anne-Karolin Ebert / Raimund Stein / Alfredo Brusco / Massimo Di Grazia / Ali Tamer / Federico M. Torres / Jose L. Hernandez / Philipp Erben / Carlo Maj /
    Jose M. Olmos / Jose A. Riancho / Carmen Valero / Isabel C. Hostettler / Henry Houlden / David J. Werring / Johannes Schumacher / Jan Gehlen / Ann-Sophie Giel / Benedikt C. Buerfent / Samara Arkani / Elisabeth Åkesson / Emilia Rotstein / Michael Ludwig / Gundela Holmdahl / Elisa Giorgio / Alfredo Berettini / David Keene / Raimondo M. Cervellione / Nina Younsi / Melissa Ortlieb / Josef Oswald / Bernhard Haid / Martin Promm / Claudia Neissner / Karin Hirsch / Maximilian Stehr / Frank-Mattias Schäfer / Eberhard Schmiedeke / Thomas M. Boemers / Iris A. L. M. van Rooij

    Communications Biology, Vol 5, Iss 1, Pp 1-

    2022  Volume 11

    Abstract: A genome-wide association study on classic bladder exstrophy reveals eight genome-wide significant loci, most of which contained genes expressed in embryonic developmental bladder stages. ...

    Abstract A genome-wide association study on classic bladder exstrophy reveals eight genome-wide significant loci, most of which contained genes expressed in embryonic developmental bladder stages.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Molecular insights into genome-wide association studies of chronic kidney disease-defining traits

    Xiaoguang Xu / James M. Eales / Artur Akbarov / Hui Guo / Lorenz Becker / David Talavera / Fehzan Ashraf / Jabran Nawaz / Sanjeev Pramanik / John Bowes / Xiao Jiang / John Dormer / Matthew Denniff / Andrzej Antczak / Monika Szulinska / Ingrid Wise / Priscilla R. Prestes / Maciej Glyda / Pawel Bogdanski /
    Ewa Zukowska-Szczechowska / Carlo Berzuini / Adrian S. Woolf / Nilesh J. Samani / Fadi J. Charchar / Maciej Tomaszewski

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 12

    Abstract: The molecular mechanisms that underlie associations in GWAS, incl. chronic kidney disease (CKD), are largely unknown. Here, the authors perform an integrative analysis of genetic, transcriptomic and epigenomic data from human kidney to pinpoint plausible ...

    Abstract The molecular mechanisms that underlie associations in GWAS, incl. chronic kidney disease (CKD), are largely unknown. Here, the authors perform an integrative analysis of genetic, transcriptomic and epigenomic data from human kidney to pinpoint plausible molecular pathways of CKD genetic associations.
    Keywords Science ; Q
    Language English
    Publishing date 2018-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Publisher Correction

    John M. Darlow / Rebecca Darlay / Mark G. Dobson / Aisling Stewart / Pimphen Charoen / Jennifer Southgate / Simon C. Baker / Yaobo Xu / Manuela Hunziker / Heather J. Lambert / Andrew J. Green / Mauro Santibanez-Koref / John A. Sayer / Timothy H. J. Goodship / Prem Puri / Adrian S. Woolf / Rajko B. Kenda / David E. Barton / Heather J. Cordell

    Scientific Reports, Vol 8, Iss 1, Pp 1-

    Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux

    2018  Volume 1

    Abstract: A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. ...

    Abstract A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Molecular insights into genome-wide association studies of chronic kidney disease-defining traits

    Xiaoguang Xu / James M. Eales / Artur Akbarov / Hui Guo / Lorenz Becker / David Talavera / Fehzan Ashraf / Jabran Nawaz / Sanjeev Pramanik / John Bowes / Xiao Jiang / John Dormer / Matthew Denniff / Andrzej Antczak / Monika Szulinska / Ingrid Wise / Priscilla R. Prestes / Maciej Glyda / Pawel Bogdanski /
    Ewa Zukowska-Szczechowska / Carlo Berzuini / Adrian S. Woolf / Nilesh J. Samani / Fadi J. Charchar / Maciej Tomaszewski

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 12

    Abstract: The molecular mechanisms that underlie associations in GWAS, incl. chronic kidney disease (CKD), are largely unknown. Here, the authors perform an integrative analysis of genetic, transcriptomic and epigenomic data from human kidney to pinpoint plausible ...

    Abstract The molecular mechanisms that underlie associations in GWAS, incl. chronic kidney disease (CKD), are largely unknown. Here, the authors perform an integrative analysis of genetic, transcriptomic and epigenomic data from human kidney to pinpoint plausible molecular pathways of CKD genetic associations.
    Keywords Science ; Q
    Language English
    Publishing date 2018-11-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Genome-wide linkage and association study implicates the 10q26 region as a major genetic contributor to primary nonsyndromic vesicoureteric reflux

    John M. Darlow / Rebecca Darlay / Mark G. Dobson / Aisling Stewart / Pimphen Charoen / Jennifer Southgate / Simon C. Baker / Yaobo Xu / Manuela Hunziker / Heather J. Lambert / Andrew J. Green / Mauro Santibanez-Koref / John A. Sayer / Timothy H. J. Goodship / Prem Puri / Adrian S. Woolf / Rajko B. Kenda / David E. Barton / Heather J. Cordell

    Scientific Reports, Vol 7, Iss 1, Pp 1-

    2017  Volume 13

    Abstract: Abstract Vesicoureteric reflux (VUR) is the commonest urological anomaly in children. Despite treatment improvements, associated renal lesions – congenital dysplasia, acquired scarring or both – are a common cause of childhood hypertension and renal ... ...

    Abstract Abstract Vesicoureteric reflux (VUR) is the commonest urological anomaly in children. Despite treatment improvements, associated renal lesions – congenital dysplasia, acquired scarring or both – are a common cause of childhood hypertension and renal failure. Primary VUR is familial, with transmission rate and sibling risk both approaching 50%, and appears highly genetically heterogeneous. It is often associated with other developmental anomalies of the urinary tract, emphasising its etiology as a disorder of urogenital tract development. We conducted a genome-wide linkage and association study in three European populations to search for loci predisposing to VUR. Family-based association analysis of 1098 parent-affected-child trios and case/control association analysis of 1147 cases and 3789 controls did not reveal any compelling associations, but parametric linkage analysis of 460 families (1062 affected individuals) under a dominant model identified a single region, on 10q26, that showed strong linkage (HLOD = 4.90; ZLRLOD = 4.39) to VUR. The ~9Mb region contains 69 genes, including some good biological candidates. Resequencing this region in selected individuals did not clearly implicate any gene but FOXI2, FANK1 and GLRX3 remain candidates for further investigation. This, the largest genetic study of VUR to date, highlights the 10q26 region as a major genetic contributor to VUR in European populations.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2017-11-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Circulating angiopoietin-2 is a marker for early cardiovascular disease in children on chronic dialysis.

    Rukshana C Shroff / Karen L Price / Maria Kolatsi-Joannou / Alexandra F Todd / David Wells / John Deanfield / Richard J Johnson / Lesley Rees / Adrian S Woolf / David A Long

    PLoS ONE, Vol 8, Iss 2, p e

    2013  Volume 56273

    Abstract: Cardiovascular disease (CVD) is increasingly recognised as a complication of childhood chronic kidney disease (CKD) even in the absence of diabetes and hypertension. We hypothesized that an alteration in angiopoietin-1 and -2, growth factors which ... ...

    Abstract Cardiovascular disease (CVD) is increasingly recognised as a complication of childhood chronic kidney disease (CKD) even in the absence of diabetes and hypertension. We hypothesized that an alteration in angiopoietin-1 and -2, growth factors which regulate endothelial and vascular function could be involved. We report that the endothelial survival factor, angiopoietin-1 is low in children with pre-dialysis CKD whereas the pro-inflammatory angiopoietin-2 is elevated in children on dialysis. In dialysis patients, angiopoietin-2 positively correlated with time on dialysis, systolic blood pressure, and carotid artery intima media thickness. Elevated angiopoietin-2 levels in dialysis versus pre-dialysis CKD patients were also associated with an anti-angiogenic (high soluble VEGFR-1 and low VEGF-A) and pro-inflammatory (high urate, E-selectin, P-selectin and VCAM-1) milieu. Ang-2 was immunodetected in arterial biopsy samples whilst the expression of VEGF-A was significantly downregulated in dialysis patients. Serum urate correlated with angiopoietin-2 levels in dialysis patients and addition of uric acid was able to induce rapid release of angiopoietin-2 from cultured endothelial cells. Thus, angiopoietin-2 is a marker for cardiovascular disease in children on chronic dialysis and may act as an anti-angiogenic and pro-inflammatory effector in this context. The possibility that the release of angiopoietin-2 from endothelia is mediated by urate should be explored further.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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