Mineralocorticoid receptor antagonism in diabetes limits albuminuria by preserving endothelial glycocalyx

The glomerular endothelial glycocalyx (GEnGlx) forms the first part of the glomerular filtration barrier (GFB). Excess mineralocorticoid receptor (MR) activation causes GEnGlx damage and albuminuria. We hypothesised that MR antagonism with spironolactone limits albuminuria in diabetes by preserving the GEnGlx. Streptozotocin-induced diabetic Wistar rats developed increased glomerular albumin permeability (Ps’alb) and albuminuria, with associated GEnGlx loss and increased plasma and urine active MMP2. Spironolactone reduced MMP2 activity, preserved the GEnGlx, restored Ps’alb to control values and prevented diabetes-induced albuminuria progression. Enzymatic degradation of the GEnGlx, with hyaluronidase, reversed the effect of spironolactone in diabetic rats, confirming the importance of GEnGlx preservation in this model. Previously, no techniques have been available to directly quantify GEnGlx damage in human disease. We validated a novel fluorescent profile peak-to-peak confocal imaging technique and applied it to assess GEnGlx damage on renal biopsies from patients with DN and compared them to healthy controls. We confirmed that dramatic GEnGlx loss occurs in human DN. This likely contributes to the increased glomerular albumin permeability seen in human DN. Taken together our work suggests GEnGlx preservation is an important mechanism of reno-protection by MR inhibitors in diabetes.