Role of vascular endothelial growth factor A in the glomerulus
Subtitle: analysis of phenotypes with glomerular-specific alterations of VEGF-A expression in murine transgenic lines
By: by Vera Eremina.
Published: 2006
Language: eng
Number of pages: 187
ISBN-13: 9780494158708
Description: Vascular Endothelial Growth Factor A (VEGF-A) is a critical mediator of vasculogenesis and angiogenesis. It is required for the establishment and maintenance of endothelial fenestrae in-vitro. Knockouts of VEGF-A or its receptors in mice result in lethality at midgestation. These early lethal phenotypes preclude the analysis of the role of VEGF-A signaling in the kidney.In the thesis, the role of VEGF-A in the development and maintenance of the glomerular filtration barrier is presented based on data from the VEGF-A transgenic mouse lines generated during my doctoral studies.To fully understand the biologic role of VEGF-A in the glomerulus, the level of VEGF-A was manipulated in fully differentiated adult glomeruli. Cre-mediated VEGF-A deletion from glomeruli of adult mice led to renal-restricted thrombotic microangiopathy and subsequent glomerulosclerosis.The Cre-loxP conditional gene targeting system and a combination of hypomorphic and null VEGF-A alleles were used to alter the gene dose of VEGF-A produced by podocytes in transgenic mice. It was demonstrated in-vivo that each VEGF-A gene dose is associated with distinct clinical and pathological phenotypes in murine models. Podocyte-specific deletion of both VEGF-A alleles leads to congenital nephropathy and perinatal lethality. Mice with podocyte-specific haploinsufficiency for all VEGF-A isoforms develop glomerular endotheliosis, the renal lesion seen in preeclampsia. Further reduction of VEGF-A leads to mesangiolysis and end stage renal disease by 3 weeks of age. Podocyte-specific overexpression of the 164 isoform of VEGF-A results in collapsing glomerulopathy, the classic lesion seen in HIV-associated nephropathy.These results provide the first genetic evidence that endogenous VEGF-A production is required for maintenance of a differentiated vascular bed and more specifically for integrity of the glomerular filtration barrier. These findings may help to explain the observation that a subset of patients treated with VEGF-A inhibitors develop proteinuria.Dysregulation of VEGF-A expression has been identified in a wide variety of renal diseases. Conversely, infusion of VEGF-A into animals with thrombotic thrombocytopenic purpura, diabetic glomerulopathy or a remnant kidney appears to be protective.
Notes: Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3589.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

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