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Hyaluronic acid plays a key role in protecting against diabetic kidney disease


   Bristol Medical School

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Brief Rationale
30-40% of patients with diabetes progress to diabetic kidney disease (DKD) within 10-15yr. This is the largest cause of end stage renal disease in the Western world and novel strategies are urgently sought. Breakdown of the ultrafiltration unit within the kidney, the glomerular capillaries, leads to the leakage of proteins such as albumin into the urine (albuminuria). Glomerular capillaries are lined with a protective gel-like layer (the endothelial glycocalyx (e-Glx)); the first barrier to protein. This layer is damaged in DKD. Our unique evidence suggests that paracrine growth factors (VEGFC and angiopoietin-1) can restore e-Glx in DKD and this is associated with reduced glomerular albumin permeability (1, 2). In vitro evidence suggests that these growth factors upregulate a component of the glomerular e-Glx; hyaluronic acid (HA) (3).

Hypothesis
HA will protect from glomerular e-Glx damage and albuminuria in DKD.

Aims and objectives
Aim 1: To promote transgenic endothelial expression of HA in experimental diabetes
Aim 2: To quantify changes to glomerular e-Glx

Methods
The PhD student will use transgenic mice and models of type 1 and type 2 diabetes. Glomerular permeability and renal function will be assessed using traditional and novel methods (that we have recently developed). Sophisticated microscopy and liquid chromatography analysis will be applied to tissue samples to quantify changes in glycocalyx depth and structure. Over expression studies will also be used in our unique human cell lines to complement in vivo work.

References

1. Desideri, S, Onions, KL, Qiu, Y, Ramnath, RD, Butler, MJ, Neal, CR, King, MLR, Salmon, AE, Saleem, MA, Welsh, GI, Michel, CC, Satchell, SC, Salmon, AHJ, Foster, RR: A novel assay provides sensitive measurement of physiologically relevant changes in albumin permeability in isolated human and rodent glomeruli. Kidney Int, 93: 1086-1097, 2018.

2. Onions, KL, Gamez, M, Buckner, NR, Baker, SL, Betteridge, KB, Desideri, S, Dallyn, BP, Ramnath, RD, Neal, CR, Farmer, LK, Mathieson, PW, Gnudi, L, Alitalo, K, Bates, DO, Salmon, AHJ, Welsh, GI, Satchell, SC, Foster, RR: VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy. Diabetes, 68: 172-187, 2019.

3. Foster, RR, Armstrong, L, Baker, S, Wong, DW, Wylie, EC, Ramnath, R, Jenkins, R, Singh, A, Steadman, R, Welsh, GI, Mathieson, PW, Satchell, SC: Glycosaminoglycan regulation by VEGFA and VEGFC of the glomerular microvascular endothelial cell glycocalyx in vitro. Am J Pathol, 183: 604-616, 2013.

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