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.
The American journal of pathology. 2016 Feb 09 [Epub ahead of print]
Marjolein Garsen, Marilen Benner, Henry Dijkman, Toin H van Kuppevelt, Jin-Ping Li, Ton J Rabelink, Israel Vlodavsky, Jo H M Berden, Angelique L W M M Rops, Michael Elkin, Johan van der Vlag
Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands. , Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands. , Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands. , Department of Biochemistry, Radboud University Medical Center, Nijmegen, the Netherlands. , Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. , Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. , Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. , Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands. , Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands. , Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. , Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
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