title: WT1-dependent sulfatase expression maintains the normal glomerular filtration barrier.
abstract: Paracrine signaling between podocytes and glomerular endothelial cells through vascular endothelial growth factor A (VEGFA) maintains a functional glomerular filtration barrier. Heparan sulfate proteoglycans (HSPGs), located on the cell surface or in the extracellular matrix, bind signaling molecules such as VEGFA and affect their local concentrations, but whether modulation of these moieties promotes normal crosstalk between podocytes and endothelial cells is unknown. Here, we found that the transcription factor Wilms' Tumor 1 (WT1) modulates VEGFA and FGF2 signaling by increasing the expression of the 6-O-endosulfatases Sulf1 and Sulf2, which remodel the heparan sulfate 6-O-sulfation pattern in the extracellular matrix. Mice deficient in both Sulf1 and Sulf2 developed age-dependent proteinuria as a result of ultrastructural abnormalities in podocytes and endothelial cells, a phenotype similar to that observed in children with WT1 mutations and in Wt1(+/-) mice. These kidney defects associated with a decreased distribution of VEGFA in the glomerular basement membrane and on endothelial cells. Collectively, these data suggest that WT1-dependent sulfatase expression plays a critical role in maintaining the glomerular filtration barrier by modulating the bioavailability of growth factors, thereby promoting normal crosstalk between podocytes and endothelial cells.
authors: Department of Medicine, Children’s Hospital Boston and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA. Valerie.Schumacher@childrens.harvard.edu
authors: Valérie A
authors: VA
authors: Schumacher
authors: Ursula
authors: U
authors: Schlötzer-Schrehardt
authors: S Ananth
authors: SA
authors: Karumanchi
authors: Xiaofeng
authors: X
authors: Shi
authors: Joseph
authors: J
authors: Zaia
authors: Stefanie
authors: S
authors: Jeruschke
authors: Dongsheng
authors: D
authors: Zhang
authors: Hermann
authors: H
authors: Pavenstädt
authors: Hermann
authors: H
authors: Pavenstaedt
authors: Astrid
authors: A
authors: Drenckhan
authors: Kerstin
authors: K
authors: Amann
authors: Carrie
authors: C
authors: Ng
authors: Sunny
authors: S
authors: Hartwig
authors: Kar-Hui
authors: KH
authors: Ng
authors: Jacqueline
authors: J
authors: Ho
authors: Jordan A
authors: JA
authors: Kreidberg
authors: Mary
authors: M
authors: Taglienti
authors: Brigitte
authors: B
authors: Royer-Pokora
authors: Xingbin
authors: X
authors: Ai
mesh_terms: D000818:Animals; D002450:Cell Communication; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D007678:Kidney Glomerulus / Q000201:enzymology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009154:Mutation; D010539:Permeability; D011401:Promoter Regions, Genetic; D013429:Sulfatases / Q000378:metabolism*; D015238:Sulfotransferases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D025721:WT1 Proteins / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D025721:WT1 Proteins; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; C486773:Sulf1 protein, mouse; D015238:Sulfotransferases; C514911:Sulf2 protein, mouse; D013429:Sulfatases