Abstract: Microalbuminuria (small quantities of albumin in the urine) indicates and predicts cardiovascular disease mortality and is the earliest clinical indicator of diabetic nephropathy (DN). All endothelial cells are coated with a negatively charged layer; the glycocalyx, damage to which is thought to cause microalbuminuria. We have shown that glomerular vascular endothelial growth factor (VEGF)C overexpression ameliorates the progression of experimental DN, associated with protection of the endothelial glycocalyx layer. We aim to show that these effects are glycocalyx-dependent. Disruption of murine endothelial glycocalyx will be induced enzymatically (acute or chronic) or by transgenic gene excision. Glomerular VEGFC expression will be induced in mice either pre glycocalyx-disruption or post-disruption or exogenous VEGFC will be given during disruption. Changes will be measured by electron microscopy, glycocalyx structural profiling, albuminuria and a novel glomerular permeability assay. Prevention from the progression of albuminuria may prevent renal complications, as well as convey important cardioprotective benefits.
Hypothesis: VEGFC-mediated protection from albuminuria is GEnC glycocalyx dependent 4. Experimental details and design of proposed investigation Aim 1: VEGFC protects against glycocalyx disruption in GEnC Aim 2: VEGFC restores glycocalyx disruption in GEnC ex vivo (A) and in vivo (B) Aim 3: VEGFC mediated rescue of albuminuria is glycocalyx dependent (A); Heparin sulphate in particular (B)
This studentship will be supervised by Dr Becky Foster and Dr Simon Satchell within the Academic Renal Unit, School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol.
When applying please select ’Medicine PhD’ within the Faculty of Health Sciences.