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The biology of kidney malformations

Winyard, Paul Julian Douglas; (0329) The biology of kidney malformations. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Kidney malformations, such as dysplastic kidneys, are the commonest cause of chronic renal failure in infants and young children. It has been suggested, based on anatomical descriptions, that failure of ureteric bud branching and mesenchymal induction leads to dysplasia, yet little is known about the underlying molecular mechanisms. In this thesis, therefore, I have examined several aspects of the cell biology of human dysplastic kidneys, and compared them with normal developing and mature kidneys. In normal developing kidneys, proliferation was prominent in the nephrogenic cortex whilst apoptosis was predominantly detected in early nephron precursors and in the medulla. The transcription factor PAX-2 was expressed in actively proliferating cells in both ureteric bud ampullae and condensing mesenchyme. In contrast, the transcription factor WT-1 and survival factor BCL-2 were solely detected in the condensing mesenchyme and developing nephrons, whilst the cell adhesion molecule galectin-3 was restricted to the ureteric bud lineage. In the mature kidney PAX-2 and BCL-2 were downregulated, whilst WT-1 expression persisted in podocytes and galectin-3 was detected in a-intercalated cells of collecting ducts. In dysplastic kidneys, proliferation was prominent in dysplastic tubules and cysts, and PAX-2, BCL-2 and galectin-3 were persistently expressed in these epithelia. Therefore, continuous proliferation signals in combination with ectopic survival factors may explain cyst formation in these 'immature' dysplastic epithelia. In contrast, apoptosis was prominent in cells in the surrounding loosely arranged 'mesenchymal' tissue. These cells expressed WT-1, but did not express PAX-2 and BCL-2 and these factors may therefore be essential for precursor survival and proliferation during nephron formation. In addition, in preliminary experiments, cells were cultured from dysplastic kidneys and transduced with a simian virus 40 (SV40) large T antigen construct. In future, culture and characterisation of these potentially immortal cells may provide a novel method to investigate the functional biology of kidney malformations.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The biology of kidney malformations
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10106540
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