Johnson, Tanya Michelle; (2001) The biology of galectin-3 in normal and cystic renal development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Galectin-3 is a 30-42 kDa [beta]-galactoside-binding lectin with putative functions in cell growth, adhesion and neoplastic transformation. Galectin-3 is expressed in the human ureteric bud / collecting duct lineage and is upregulated in human autosomal recessive kidney disease (ARPKD). ARPKD is a congenital kidney malformation that affects 1 in 40,000 births, whereby cysts develop from the collecting ducts. Previous investigations have shown that exogenous galectin-3 protein levels modulates the growth of cysts derived from Madin Darby Canine Kidney (MDCK) collecting duct-derived cells in vitro. In this thesis, therefore, I investigated the expression patterns and functions of galectin-3 in normal mouse kidney development, and in an animal model for ARPKD, the cpk/cpk mouse. I also begun preliminary investigations into the roles of galectin-3 in kidney regeneration, following acute renal failure. During normal mouse development, galectin-3 protein was detected in the developing ureteric bud / collecting duct lineage, and downregulated in mature postnatal collecting ducts. Utilising mouse metanephric organ culture, I functionally implicated galectin-3 in the control of ureteric bud branching by demonstrating retardation of ureteric bud branching and decreased nephron formation, when extracellular galectin-3 protein levels were altered. (Bullock et al. 2001). In cystic kidneys postnatally, galectin-3 expression patterns, as assessed by in situ hybridisation, immunohistochemistry and western blot, was markedly upregulated in collecting duct derived cysts from the cpk / cpk mice. Paclitaxel (Taxol), a microtubule-stabilising drug, had previously demonstrated therapeutic affects which reduced cyst growth in vivo. Therefore during these investigations, I sought to investigate the effects of paclitaxel on galectin-3 expression within aberrant cystic epithelia. Paclitaxel treatment delayed cyst development and this was associated with decreased expression of galectin-3 in vivo and increased secretion of galectin-3, into the medium, by cystic epithelial cells in-vitro. Based on these results, I propose that in normal development, galectin-3 is implicated in normal ureteric bud differentiation, and upregulation of galectin-3 is associated with the aberrant growth and expansion of cystic collecting duct epithelia in ARPKD.

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