WT1-dependent sulfatase expression maintains the normal glomerular filtration barrier

Schumacher VA, Schlötzer-Schrehardt U, Karumanchi SA, Shi X, Zaia J, Jeruschke S, Zhang D, Pavenstaedt H, Drenckhan A, Amann KU, Ng C, Hartwig S, Ng KH, Ho J, Kreidberg JA, Taglienti M, Royer-Pokora B, Ai X (2011)

Publication Type: Journal article

Publication year: 2011

Journal

Journal of the American Society of Nephrology American Society of Nephrology

Book Volume: 22

Pages Range: 1286-96

Journal Issue: 7

DOI: 10.1681/ASN.2010080860

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 with CRIS profile

Ursula Schlötzer-Schrehardt Medizinische Fakultät Kerstin Ute Amann Department of Nephropathology

Additional Organisation(s)

Department of Ophthalmology

Involved external institutions

Boston Children's Hospital US United States (USA) (US) Harvard University US United States (USA) (US) Boston University US United States (USA) (US) Heinrich-Heine-Universität Düsseldorf DE Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE)

How to cite

APA:

Schumacher, V.A., Schlötzer-Schrehardt, U., Karumanchi, S.A., Shi, X., Zaia, J., Jeruschke, S.,... Ai, X. (2011). WT1-dependent sulfatase expression maintains the normal glomerular filtration barrier. Journal of the American Society of Nephrology, 22(7), 1286-96. https://doi.org/10.1681/ASN.2010080860

MLA:

Schumacher, Valerie A., et al. "WT1-dependent sulfatase expression maintains the normal glomerular filtration barrier." Journal of the American Society of Nephrology 22.7 (2011): 1286-96.

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