Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy

The selective endothelin A receptor antagonist, atrasentan, has been shown to reduce albuminuria in type 2 diabetes mellitus. We previously showed that the structural integrity of a glomerular endothelial glycocalyx is required to prevent albuminuria. Therefore we tested in diabetic apolipoprotein E deficient mice, the potential of atrasentan to stabilize the endothelial glycocalyx in relation to its anti-albuminuric effects. Treatment with atrasentan (7.5mg/kg/day) for four weeks, reduced urinary albumin-creatinine ratios with 26.0±6.5% (p In vitro experiments of endothelial cells exposed to laminar flow and co-cultured with pericytes, confirmed that atrasentan reduced endothelial heparanase expression and increased glycocalyx thickness in the presence of a diabetic milieu. Together these data point towards a role for restoration of endothelial function and tissue homeostasis in the anti-albuminuric effects of atrasentan, and provide a mechanistic explanation for the clinical observations on lowering of albuminuria with atrasentan in diabetic nephropathy.