Vitamin D attenuates proteinuria by inhibition of heparanase expression in the podocyte
| Autor: | Angelique L.W.M.M. Rops, Joost G. J. Hoenderop, Tom Nijenhuis, Marjolein Garsen, Jo H. M. Berden, Ramon Sonneveld, Toin H. van Kuppevelt, Johan van der Vlag, Ton J. Rabelink, Suzanne Huntink |
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| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Proteinuria urogenital system Chemistry Glomerular basement membrane urologic and male genital diseases medicine.disease Calcitriol receptor female genital diseases and pregnancy complications Pathology and Forensic Medicine Podocyte Diabetic nephropathy medicine.anatomical_structure Endocrinology Internal medicine medicine Glomerular Filtration Barrier Vitamin D and neurology Heparanase medicine.symptom |
| Zdroj: | The Journal of Pathology. 237:472-481 |
| ISSN: | 0022-3417 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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