AbstractAldosterone contributes to end organ damage in heart failure and renal disease. Spironolactone, a mineralocorticoid receptor inhibitor, slows disease progression but side effects including hyperkalemia limit its use. Damage to the endothelial glycocalyx (a luminal biopolymer layer) has been implicated in pathogenesis of endothelial dysfunction and albuminuria, but to date no one has investigated if the glomerular endothelial glycocalyx is affected by aldosterone or if the beneficial actions of spironolactone in diabetic nephropathy are mediated through glycocalyx preservation.
In vitro human glomerular endothelial cells exposed to 0.1nM aldosterone and 145mMol NaCl exhibited reduced cell surface glycocalyx components (heparan sulphate and syndecan 4) and disrupted shear sensing consistent with glycocalyx damage. In vivo 0.6μg/g/day of aldosterone (subcutaneous minipump) and 1% NaCl drinking water caused albuminuria in two mouse strains. We subsequently developed an intravital multiphoton imaging technique to confirm that aldosterone caused; glomerular endothelial glycocalyx damage and increased the glomerular albumin sieving coefficient. Targeting matrix metalloproteinases 2 and 9 with a specific inhibitor preserved the glycocalyx, blocked the rise in the glomerular albumin sieving coefficient and prevented albuminuria. In addition we have demonstrated that the mineralocorticoid receptor inhibitor, spironolactone, when started early in the diabetic disease course, can reverse the development of proteinuria, reduce the glomerular albumin permeability to control levels, and preserve the glomerular endothelial glycocalyx.
Damage to the glomerular endothelial glycocalyx occurred in both animal models. Spironolactone or MMP2/9 inhibition prevented albuminuria, preserved the glomerular endothelial glycocalyx and reduced glomerular albumin leakage. Together these data suggest that preservation of the glomerular endothelial glycocalyx may represent a novel strategy for limiting the pathological effects of salt and aldosterone excess and diabetes. Glycocalyx targeted therapy will be free from the inherent risk of hyperkalemia associated with mineralocorticoid receptor blockade and so could represent a valuable clinical therapy in the future.
|Date of Award||25 Sep 2018|
|Supervisor||Simon C Satchell (Supervisor) & R R Foster (Supervisor)|