• Margien G S Boels, M Cristina Avramut, Angela Koudijs, Martijn J C Dane, Dae Hyun Lee, Johan van der Vlag, Abraham J Koster, Anton Jan van Zonneveld, Ernst van Faassen, Hermann-Josef Gröne, Bernard M van den Berg, and Ton J Rabelink.
• Einthoven Laboratory for Experimental Vascular Medicine, Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands m.g.s.boels@lumc.nl.
• Diabetes. 2016 Aug 1; 65 (8): 2429-39.

AbstractAtrasentan, a selective endothelin A receptor antagonist, has been shown to reduce albuminuria in type 2 diabetes. We previously showed that the structural integrity of a glomerular endothelial glycocalyx is required to prevent albuminuria. Therefore we tested the potential of atrasentan to stabilize the endothelial glycocalyx in diabetic apolipoprotein E (apoE)-deficient mice in relation to its antialbuminuric effects. Treatment with atrasentan (7.5 mg/kg/day) for 4 weeks reduced urinary albumin-to-creatinine ratios by 26.0 ± 6.5% (P < 0.01) in apoE knockout (KO) mice with streptozotocin-induced diabetes consuming an atherogenic diet, without changes in gross glomerular morphology, systemic blood pressure, and blood glucose concentration. Endothelial cationic ferritin surface coverage, investigated using large-scale digital transmission electron microscopy, revealed that atrasentan treatment increases glycocalyx coverage in diabetic apoE KO mice from 40.7 ± 3.2% to 81.0 ± 12.5% (P < 0.05). This restoration is accompanied by increased renal nitric oxide concentrations, reduced expression of glomerular heparanase, and a marked shift in the balance of M1 and M2 glomerular macrophages. In vitro experiments with endothelial cells exposed to laminar flow and cocultured with pericytes confirmed that atrasentan reduced endothelial heparanase expression and increased glycocalyx thickness in the presence of a diabetic milieu. Together these data point toward a role for the restoration of endothelial function and tissue homeostasis through the antialbuminuric effects of atrasentan, and they provide a mechanistic explanation for the clinical observations of reduced albuminuria with atrasentan in diabetic nephropathy.© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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