title: Vitamin D attenuates proteinuria by inhibition of heparanase expression in the podocyte.
abstract: The glomerular filtration barrier consists of podocytes, the glomerular basement membrane, and endothelial cells covered with a glycocalyx. Heparan sulphate (HS) in the glomerular filtration barrier is reduced in patients with proteinuria, which is associated with increased expression of the HS-degrading enzyme heparanase. Previously, we showed that heparanase is essential for the development of proteinuria in experimental diabetic nephropathy. Vitamin D supplementation reduces podocyte loss and proteinuria in vitro and in vivo. Therefore, we hypothesize that vitamin D reduces proteinuria by reducing glomerular heparanase. Adriamycin-exposed rats developed proteinuria and showed increased heparanase expression, which was reduced by 1,25-dihydroxyvitamin D3 (1,25-D3) treatment. In vitro, adriamycin increased heparanase mRNA in the podocyte, which could be corrected by 1,25-D3 treatment. In addition, 1,25-D3 treatment reduced transendothelial albumin passage after adriamycin stimulation. In line with these results, we showed direct binding of the vitamin D receptor to the heparanase promoter, and 1,25-D3 dose-dependently reduced heparanase promoter activity. Finally, 1,25-D3-deficient 25-hydroxy-1α-hydroxylase knockout mice developed proteinuria and showed increased heparanase, which was normalized by 1,25-D3 treatment. Our data suggest that the protective effect of vitamin D on the development of proteinuria is mediated by inhibiting heparanase expression in the podocyte.
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: Ramon
authors.initials: R
authors.lastname: Sonneveld
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: Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Huntink
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 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: Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
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: Tom
authors.initials: T
authors.lastname: Nijenhuis
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D005966:Glucuronidase / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology*; D011507:Proteinuria / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D000099175:Heparanase
chemical_list: D002117:Calcitriol; D005966:Glucuronidase; D006497:Heparan Sulfate; D000099175:Heparanase
keywords: heparanase; podocyte; proteinuria; vitamin D