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Vitamin D attenuates proteinuria by inhibition of heparanase expression in the podocyte
Author(s) -
Garsen Marjolein,
Sonneveld Ramon,
Rops Angelique LWMM,
Huntink Suzanne,
van Kuppevelt Toin H,
Rabelink Ton J,
Hoenderop Joost GJ,
Berden Jo HM,
Nijenhuis Tom,
van der Vlag Johan
Publication year - 2015
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4593
Subject(s) - heparanase , podocyte , proteinuria , medicine , endocrinology , glomerular basement membrane , chemistry , heparan sulfate , kidney , heparin
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 D 3 (1,25‐ D 3 ) treatment. In vitro , adriamycin increased heparanase mRNA in the podocyte, which could be corrected by 1,25‐ D 3 treatment. In addition, 1,25‐ D 3 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‐ D 3 dose‐dependently reduced heparanase promoter activity. Finally, 1,25‐ D 3 ‐deficient 25‐hydroxy‐1α‐hydroxylase knockout mice developed proteinuria and showed increased heparanase, which was normalized by 1,25‐ D 3 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. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.