Endothelial glycocalyx restoration to prevent proteinuria-associated vascular damage

Cardiovascular disease is the leading cause of premature death in chronic kidney disease, and proteinuria is an independent risk factor of cardiovascular mortality. Reducing proteinuria can prevent cardiovascular complications, suggesting a causative link. Blood vessels are coated with a protective layer, the endothelial glycocalyx (eGlx).

Damage to eGlx results in vascular leak of protein, including in glomeruli (proteinuria). Proteinuric kidney diseases are associated with widespread vascular dysfunction and eGlx damage. We have shown that targeting eGlx can restore vascular integrity in the glomerular and systemic circulation.

Our preliminary data shows directly that proteinuria, caused by targeted glomerular podocyte damage (5-1-6 nephropathy), results in increased systemic vascular leak. This is correlated with decreased eGlx depth.

Heparanase (HPSE), which cleaves heparan sulphate (HS), an essential component of eGlx, is upregulated by injured podocytes in proteinuric disease. We hypothesise that podocyte-induced HPSE upregulation causes vascular eGlx damage in proteinuric disease.

Firstly, we will confirm that podocyte injury in our 5-1-6 nephropathy model increases glomerular and systemic HPSE upregulation/activity.

Secondly, we will demonstrate that increased podocyte-induced HPSE upregulation/activity is critical for vascular eGlx damage and, finally, we will demonstrate that HPSE inhibition is a novel therapeutic approach to prevent proteinuria-associated vascular damage.