title: Heparanase Is Essential for the Development of Acute Experimental Glomerulonephritis.
abstract: Heparanase, a heparan sulfate (HS)--specific endoglucuronidase, mediates the onset of proteinuria and renal damage during experimental diabetic nephropathy. Glomerular heparanase expression is increased in most proteinuric diseases. Herein, we evaluated the role of heparanase in two models of experimental glomerulonephritis, being anti-glomerular basement membrane and lipopolysaccharide-induced glomerulonephritis, in wild-type and heparanase-deficient mice. Induction of experimental glomerulonephritis led to an increased heparanase expression in wild-type mice, which was associated with a decreased glomerular expression of a highly sulfated HS domain, and albuminuria. Albuminuria was reduced in the heparanase-deficient mice in both models of experimental glomerulonephritis, which was accompanied by a better renal function and less renal damage. Notably, glomerular HS expression was preserved in the heparanase-deficient mice. Glomerular leukocyte and macrophage influx was reduced in the heparanase-deficient mice, which was accompanied by a reduced expression of both types 1 and 2 helper T-cell cytokines. In vitro, tumor necrosis factor-α and lipopolysaccharide directly induced heparanase expression and increased transendothelial albumin passage. Our study shows that heparanase contributes to proteinuria and renal damage in experimental glomerulonephritis by decreasing glomerular HS expression, enhancing renal leukocyte and macrophage influx, and affecting the local cytokine milieu.
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Garsen
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Marilen
authors.initials: M
authors.lastname: Benner
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Henry B
authors.initials: HB
authors.lastname: Dijkman
authors.affiliation: Department of Biochemistry, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.affiliation: Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Jo H M
authors.initials: JH
authors.lastname: Berden
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Angelique L W M M
authors.initials: AL
authors.lastname: Rops
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Elkin
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address: johan.vandervlag@radboudumc.nl.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
mesh_terms: D000208:Acute Disease; D000818:Animals; D003928:Diabetic Nephropathies / Q000378:metabolism*; D050533:Glomerular Basement Membrane / Q000378:metabolism*; D005921:Glomerulonephritis / Q000209:etiology* / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011507:Proteinuria / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006497:Heparan Sulfate; D014409:Tumor Necrosis Factor-alpha; D000099175:Heparanase