WT1-Dependent Sulfatase Expression Maintains the Normal Glomerular Filtration Barrier

• Published in: Journal of the American Society of Nephrology Vol. 22; no. 7; pp. 1286 - 1296
• Main Authors: SCHUMACHER, Valérie A, SCHLÖTZER-SCHREHARDT, Ursula, NG, Carrie, HARTWIG, Sunny, NG, Kar-Hui, HO, Jacqueline, KREIDBERG, Jordan A, TAGLIENTI, Mary, ROYER-POKORA, Brigitte, XINGBIN AI, ANANTH KARUMANCHI, S, XIAOFENG SHI, ZAIA, Joseph, JERUSCHKE, Stefanie, DONGSHENG ZHANG, PAVENSTAEDT, Hermann, DRENCKHAN, Astrid, AMANN, Kerstin
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.07.2011
• Subjects: Animals; Basic Research; Biological and medical sciences; Cell Communication; Fibroblast Growth Factor 2 - metabolism; Gene Expression Regulation; Heterozygote; Humans; Kidney Glomerulus - enzymology; Medical sciences; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mutation; Nephrology. Urinary tract diseases; Permeability; Promoter Regions, Genetic; Sulfatases - metabolism; Sulfotransferases - metabolism; Vascular Endothelial Growth Factor A - metabolism; WT1 Proteins - metabolism; Nephrology; Glomerular filtration; Enzyme; Arylsulfatase; Hydrolases; Esterases; Wilms tumor gene; Sulfuric ester hydrolases; Normal; Urology; Tumor suppressor gene
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2010080860

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.