title: Endothelin-1 Induces Proteinuria by Heparanase-Mediated Disruption of the Glomerular Glycocalyx.
abstract: Diabetic nephropathy (DN) is the leading cause of CKD in the Western world. Endothelin receptor antagonists have emerged as a novel treatment for DN, but the mechanisms underlying the protective effect remain unknown. We previously showed that both heparanase and endothelin-1 are essential for the development of DN. Here, we further investigated the role of these proteins in DN, and demonstrated that endothelin-1 activates podocytes to release heparanase. Furthermore, conditioned podocyte culture medium increased glomerular transendothelial albumin passage in a heparanase-dependent manner. In mice, podocyte-specific knockout of the endothelin receptor prevented the diabetes-induced increase in glomerular heparanase expression, consequent reduction in heparan sulfate expression and endothelial glycocalyx thickness, and development of proteinuria observed in wild-type counterparts. Our data suggest that in diabetes, endothelin-1 signaling, as occurs in endothelial activation, induces heparanase expression in the podocyte, damage to the glycocalyx, proteinuria, and renal failure. Thus, prevention of these effects may constitute the mechanism of action of endothelin receptor blockers in DN.
authors.affiliation: Departments of Nephrology.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Garsen
authors.affiliation: Paris Cardiovascular Research Centre, Institut de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Olivia
authors.initials: O
authors.lastname: Lenoir
authors.affiliation: Departments of Nephrology.
authors.forename: Angelique L W M M
authors.initials: AL
authors.lastname: Rops
authors.affiliation: Pathology, and.
authors.forename: Henry B
authors.initials: HB
authors.lastname: Dijkman
authors.affiliation: Pathology, and.
authors.forename: Brigith
authors.initials: B
authors.lastname: Willemsen
authors.affiliation: Biochemistry, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Department of Nephrology, Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.affiliation: Departments of Nephrology.
authors.forename: Jo H M
authors.initials: JH
authors.lastname: Berden
authors.affiliation: Paris Cardiovascular Research Centre, Institut de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.affiliation: Departments of Nephrology, Johan.vanderVlag@radboudumc.nl.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology; D019332:Endothelin-1 / Q000502:physiology*; D005966:Glucuronidase / Q000502:physiology*; D019276:Glycocalyx / Q000201:enzymology*; D007678:Kidney Glomerulus / Q000201:enzymology* / Q000648:ultrastructure*; D008297:Male; D051379:Mice; D050199:Podocytes / Q000201:enzymology; D011507:Proteinuria / Q000209:etiology*; D000099175:Heparanase
chemical_list: D019332:Endothelin-1; D005966:Glucuronidase; D000099175:Heparanase
keywords: diabetic nephropathy; glomerular endothelial cells; glomerular filtration barrier; podocyte; proteinuria