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Angiopoietin growth factors in models of renal disease

Long, David Andrew; (2003) Angiopoietin growth factors in models of renal disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Angiopoietin (Ang) growth factors modulate endothelial survival and morphogenesis, actions depending on an interplay of agonistic (Ang-1) and antagonistic (Ang-2) angiopoietins with their Tie-2 receptor tyrosine kinase and vascular endothelial growth factor (VEGF) signalling through VEGF receptor 2. Emerging data suggests that Ang1 stabilizes capillaries. In contrast Ang2 disrupts vessels, facilitating sprouting when ambient VEGF is high but causing regression when ambient VEGF is low. My study has determined the expression of the angiopoietin family in a model of acute nephrotoxicity induced by administration of folic acid. In this model there was increased endothelial cell turnover in renal peritubular capillaries following injection of folic acid. This microvascular remodelling was accompanied by de novo expression of immunoreactive Ang-1 in regenerating distal convoluted tubules (DCT) and increased Ang-1 on western blot. This suggested a potential paracrine system between renal tubular epithelia releasing Ang and peritubular capillaries, which expressed the Tie-2 receptor in folic acid induced nephrotoxicity. I hypothesised that cytokines may regulate the expression of Ang in renal epithelia in folic acid induced nephrotoxicity. Immunostaining for macrophages, neutrophils and T-lymphocytes showed a modest increase in these cell populations in the first few days after folic acid injection. In addition, immunoreactive TNF-α was detected in the vicinity of a subset of cortical tubules, most likely DCT, from the first few days after induction of nephrotoxicity Finally, immortalised murine DCT cells were investigated. Conditioned media from DCT cells stimulated with TNF-α reduced Tie-2 phosphorylation when added to endothelial cells versus conditioned media from DCT cells with no added TNF-α. As TNF-α also decreased VEGF immunoreactivity in medium conditioned by these renal epithelia, I propose that this cytokine, which is upregulated in several experimental models of renal injury, may encourage an anti-angiogenic milieu with decreased capillary stability and microvascular regression. Hence, these in-vitro and in-vivo experiments add to the current evidence about the role of the angiopoietins in models of renal disease and also the mechanisms by which these effects are achieved.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Angiopoietin growth factors in models of renal disease
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Angiopoietin
URI: https://discovery.ucl.ac.uk/id/eprint/10102645
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