title: Endothelial Nitric Oxide Synthase Prevents Heparanase Induction and the Development of Proteinuria.
abstract: Endothelial nitric oxide synthase (eNOS) deficiency exacerbates proteinuria and renal injury in several glomerular diseases, but the underlying mechanism is not fully understood. We recently showed that heparanase is essential for the development of experimental diabetic nephropathy and glomerulonephritis, and hypothesize that heparanase expression is regulated by eNOS. Here, we demonstrate that induction of adriamycin nephropathy (AN) in C57BL/6 eNOS-deficient mice leads to an increased glomerular heparanase expression accompanied with overt proteinuria, which was not observed in the AN-resistant wild type counterpart. In vitro, the eNOS inhibitor asymmetric dimethylarginine (ADMA) induced heparanase expression in cultured mouse glomerular endothelial cells. Moreover, ADMA enhanced transendothelial albumin passage in a heparanase-dependent manner. We conclude that eNOS prevents heparanase induction and the development of proteinuria.
authors: Department of Nephrology, Radboud university medical center, Nijmegen, The Netherlands.
authors: Marjolein
authors: M
authors: Garsen
authors: Department of Nephrology, Radboud university medical center, Nijmegen, The Netherlands.
authors: Angelique L
authors: AL
authors: Rops
authors: Department of Anatomy and developmental Biology, Monash University, Clayton, Victoria, Australia.
authors: Jinhua
authors: J
authors: Li
authors: Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Katrien
authors: K
authors: van Beneden
authors: Department of Human Anatomy, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium.
authors: Christiane
authors: C
authors: van den Branden
authors: Department of Nephrology, Radboud university medical center, Nijmegen, The Netherlands.
authors: Jo Hm
authors: JH
authors: Berden
authors: Department of Nephrology, Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors: Ton J
authors: TJ
authors: Rabelink
authors: Department of Nephrology, Radboud university medical center, Nijmegen, The Netherlands.
authors: Johan
authors: http://orcid.org/0000-0001-7843-5918
authors: J
authors: van der Vlag
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011507:Proteinuria / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D000099175:Heparanase
chemical_list: D000418:Albumins; D001120:Arginine; D004317:Doxorubicin; D005966:Glucuronidase; D052250:Nitric Oxide Synthase Type III; D000099175:Heparanase; C018524:N,N-dimethylarginine