title: Atrasentan Reduces Albuminuria by Restoring the Glomerular Endothelial Glycocalyx Barrier in Diabetic Nephropathy.
abstract: Atrasentan, 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.
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands m.g.s.boels@lumc.nl.
authors.forename: Margien G S
authors.initials: MG
authors.lastname: Boels
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Avramut
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Koudijs
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Martijn J C
authors.initials: MJ
authors.lastname: Dane
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Koster
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Anton Jan
authors.initials: AJ
authors.lastname: van Zonneveld
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Ernst
authors.initials: E
authors.lastname: van Faassen
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Bernard M
authors.initials: BM
authors.lastname: van den Berg
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
mesh_terms: D000419:Albuminuria / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000077868:Atrasentan; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D065128:Endothelin Receptor Antagonists / Q000627:therapeutic use*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007678:Kidney Glomerulus / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011759:Pyrrolidines / Q000627:therapeutic use*
chemical_list: D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D000077868:Atrasentan