4 results on '"Koziell, Ania"'
Search Results
2. Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease.
- Author
-
Lennon, Rachel, Stuart, Helen, Bierzynska, Agnieszka, Randles, Michael, Kerr, Bronwyn, Hillman, Katherine, Batra, Gauri, Campbell, Joanna, Storey, Helen, Flinter, Frances, Koziell, Ania, Welsh, Gavin, Saleem, Moin, Webb, Nicholas, and Woolf, Adrian
- Subjects
KIDNEY diseases ,NEPHRITIS ,CHRONIC kidney failure ,ELECTRON microscopy ,EPITHELIAL cells ,FEVER ,HEMATURIA ,KIDNEY glomerulus ,BASAL lamina ,GENETIC mutation ,NEPHROTIC syndrome ,PROTEINURIA ,RESEARCH funding ,PHENOTYPES ,BIOINFORMATICS ,SEVERITY of illness index ,FAMILY history (Medicine) ,DATA analysis software ,DESCRIPTIVE statistics ,SEQUENCE analysis ,GENETICS - Abstract
Background: Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults and children. Investigation of familial cases has helped to build understanding of both normal physiology and disease. Methods: We investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies. Results: We report striking variability in severity of nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried a mutant COL4A5 allele, p.(Gly953Val) and p.(Gly1033Arg). Two boys had signs limited to hematuria and mild/moderate proteinuria. In striking contrast, a sister presented with end-stage renal disease (ESRD) at 8 years of age and an infant brother presented with nephrotic syndrome, progressing to ESRD by 3 years of age. Both were subsequently found to have homozygous variants in MYO1E, p.(Lys118Glu) and p.(Thr876Arg). MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein-protein interactions to intracellular myosin 1E. Conclusions: COL4A5 and MYO1E mutations may summate to perturb common signaling pathways, resulting in more severe disease than anticipated independently. We suggest screening for MYO1E and other non- COL4 'podocyte gene' mutations in XLAS when clinical nephropathy is more severe than expected for an individual's age and sex. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
3. Nephrin Is Critical for the Action of Insulin on Human Glomerular Podocytes.
- Author
-
Coward, Richard J. M., Welsh, Gavin I., Koziell, Ania, Hussain, Sagair, Lennon, Rachel, Ni, Lan, Tavaré, Jeremy M., Mathieson, Peter W., and Saleem, Moin A.
- Subjects
INSULIN ,PROTEINS ,ALBUMINURIA ,KIDNEY diseases ,CELLS - Abstract
The leading causes of albuminuria and end-stage renal failure are secondary to abnormalities in the production or cellular action of insulin, including diabetes and hyperinsulinemic metabolic syndrome. The human glomerular podocyte is a critical cell for maintaining the filtration barrier of the kidney and preventing albuminuria. We have recently shown this cell to be insulin sensitive with respect to glucose uptake, with kinetics similar to muscle cells. We now show that the podocyte protein nephrin is essential for this process. Conditionally immortalized podocytes from two different patients with nephrin mutations (natural human nephrin mutant models) were unresponsive to insulin. Knocking nephrin down with siRNA in wild-type podocytes abrogated the insulin response, and stable nephrin transfection of nephrin-deficient podocytes rescued their insulin response. Mechanistically, we show that nephrin allows the GLUT1- and GLUT4-rich vesicles to fuse with the membrane of this cell. Furthermore, we show that the COOH of nephrin interacts with the vesicular SNARE protein VAMP2 in vitro and ex vivo (using yeast-2 hybrid and coimmunoprecipitation studies). This work demonstrates a previously unsuspected role of nephrin in vesicular docking and insulin responsiveness of podocytes. Diabetes 56:1127-1135, 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
4. The human glomerular podocyte is a novel target for insulin action.
- Author
-
Coward, Richard J. M., Welsh, Gavin I., Yang, Jing, Tasman, Candida, Lennon, Rachel, Koziell, Ania, Satchell, Simon, Holman, Geoffrey D., Kerjaschki, Dontscho, Tavaré, Jeremy M., Mathieson, Peter W., Saleem, Moin A., and Tavaré, Jeremy M
- Subjects
ALBUMINURIA ,DIABETES complications ,DIABETIC nephropathies ,INSULIN resistance ,GLOMERULAR filtration rate ,ACTIN ,CYTOSKELETON ,KIDNEY diseases ,ENDOCRINE diseases ,GLUCOSE metabolism ,MUSCLE protein metabolism ,ANIMAL experimentation ,BIOLOGICAL transport ,CARRIER proteins ,CELL lines ,CELLULAR signal transduction ,COMPARATIVE studies ,CYTOPLASM ,DOSE-effect relationship in pharmacology ,EPITHELIAL cells ,GENES ,INSULIN ,RESEARCH methodology ,MEDICAL cooperation ,MICE ,PHOSPHORYLATION ,RESEARCH ,EVALUATION research - Abstract
Microalbuminuria is significant both as the earliest stage of diabetic nephropathy and as an independent cardiovascular risk factor in nondiabetic subjects, in whom it is associated with insulin resistance. The link between disorders of cellular insulin metabolism and albuminuria has been elusive. Here, we report using novel conditionally immortalized human podocytes in vitro and human glomeruli ex vivo that the podocyte, the principal cell responsible for prevention of urinary protein loss, is insulin responsive and able to approximately double its glucose uptake within 15 min of insulin stimulation. Conditionally immortalized human glomerular endothelial cells do not respond to insulin, suggesting that insulin has a specific effect on the podocyte in the glomerular filtration barrier. The insulin response of the podocyte occurs via the facilitative glucose transporters GLUT1 and GLUT4, and this process is dependent on the filamentous actin cytoskeleton. Insulin responsiveness in this key structural component of the glomerular filtration barrier may have central relevance for understanding of diabetic nephropathy and for the association of albuminuria with states of insulin resistance. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.