Huang, JL;
(2013)
Polycystic kidney disease and the renal circulation.
Doctoral thesis , UCL (University College London).
Abstract
Polycystic kidney disease (PKD) is the most common inherited cause of kidney failure affecting 1 in 1000 adults and children worldwide. Many studies focus on the disrupted cellular functions within the cyst epithelia but promising therapeutic strategies have not yet translated to clinically approved treatments for human PKD. This thesis takes a different approach and hypothesised that cyst growth requires the support of the underlying renal microvasculature and that targeting vessels could be an alternative therapeutic strategy. The renal vasculature in cystic and wild-type kidneys was first characterised using a mouse model of autosomal recessive PKD (ARPKD). It was found that mRNA levels of markers of blood and lymphatic endothelium were altered in cystic kidneys compared with wild-type. By immunohistochemistry, there was disorganisation of the vasculature with expansion of lymphatic capillaries surrounding the smaller cysts and regression of the microvasculature surrounding the larger cysts. Overall, the peri-cystic microvasculature shifted from a blood to a lymphatic endothelial phenotype. To test the potential of targeting the renal vasculature as a treatment for PKD, vascular endothelial growth factor-C (VEGFC) was administered to mouse models of both ARPKD and autosomal dominant PKD (ADPKD). The treatment significantly reduced disease severity as measured by kidney/body weight ratio by at least 28% in both models. In the model of ADPKD, serum blood urea nitrogen was also significantly reduced by around 35% indicating an improvement in renal function. Measurement of cyst characteristics revealed improvements in percentage cyst area, total number of cysts per kidney and the average cyst size. The treatment also restored normal renal vascular patterning and decreased the number of CD206+ macrophage cells which contribute to cyst growth. This thesis suggests that targeting the renal vasculature could be a therapy for PKD, with the potential to enhance current approaches.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Polycystic kidney disease and the renal circulation |
| Language: | English |
| Additional information: | Permission for digitisation not received. |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1416827 |
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