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Inflammatory mediators in normal and abnormal renal development

Cale, Catherine Mary; (1999) Inflammatory mediators in normal and abnormal renal development. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Many molecules and cells that are an integral part of the immune response in the mature organism are present in the fetus, but their roles in organogenesis are incompletely understood. This Thesis investigated tumour necrosis factor-α (TNF-α) in normal and abnormal nephrogenesis. TNF-α and its receptors were detected throughout murine nephrogenesis. In metanephric culture, exogenous TNF- α inhibited nephrogenesis, with decreased organ size, cell number, ureteric bud branching and nephron formation. This was accompanied by an increase in apoptosis on day 1 of culture, but with no effects on proliferation. Expression patterns of the transcription factors pax-2 and wt-1 in TNF-α treated cultures suggested that the factor acted on their down-stream targets. Macrophages capable of active phagocytosis were also demonstrated within metanephroi and their numbers increased in culture, with an excess increase in TNF-α treated cultures compared to controls. These cells may mask increases in apoptosis in culture and might contribute directly to abnormal metanephric development. A role for endogenous TNF-α was not established in these experiments, as neutralising its actions had no effects on metanephric cultures. The phenotype of TNF-α treated metanephroi resembled that of human renal dysplasia, a common cause of renal failure in childhood. Temporally and spatially restricted expression of TNF-α and its receptors was demonstrated in normal human fetal metanephroi. This was disrupted in dysplastic tissues, with persistent endothelial and aberrant epithelial expression of TNF receptor 2. The normal distribution of macrophages and T cells in the developing kidney was also documented, and was shown to be abnormal in renal dysplasia. In addition, fetal and postnatal dysplastic kidneys expressed both neural cell and intercellular adhesion molecules in patterns that were only seen in early fetal life in normal nephrogenesis. This work suggests, therefore, that TNF-α and inflammatory cells may contribute to the pathogenesis of renal dysplasia.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Inflammatory mediators in normal and abnormal renal development
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; TNF-alpha
URI: https://discovery.ucl.ac.uk/id/eprint/10114450
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