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PMID:21719793

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Citation

Schumacher, VA, Schlötzer-Schrehardt, U, Karumanchi, SA, Shi, X, Zaia, J, Jeruschke, S, Zhang, D, Pavenstädt, H, Pavenstaedt, H, Drenckhan, A, Amann, K, Ng, C, Hartwig, S, Ng, KH, Ho, J, Kreidberg, JA, Taglienti, M, Royer-Pokora, B and Ai, X (2011) WT1-dependent sulfatase expression maintains the normal glomerular filtration barrier. J. Am. Soc. Nephrol. 22:1286-96

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.

Links

PubMed PMC3137576 Online version:10.1681/ASN.2010080860

Keywords

Animals; Cell Communication; Fibroblast Growth Factor 2/metabolism; Gene Expression Regulation; Heterozygote; Humans; Kidney Glomerulus/enzymology; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mutation; Permeability; Promoter Regions, Genetic; Sulfatases/metabolism; Sulfotransferases/metabolism; Vascular Endothelial Growth Factor A/metabolism; WT1 Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:WT1

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:Q8K007)
  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:WT1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q8K007)

Seeded From UniProt

complete

MOUSE:SULF2

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8K007

P

  • occurs_in:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF2

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF2

involved_in

GO:0040037: negative regulation of fibroblast growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8K007

P

  • occurs_in:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF1

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8CFG0

P

  • occurs_in:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF1

involved_in

GO:0040037: negative regulation of fibroblast growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8CFG0

P

  • occurs_in:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF1

involved_in

GO:0003094: glomerular filtration

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8CFG0

P

Seeded From UniProt

complete

MOUSE:SULF1

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF1

involved_in

GO:0040037: negative regulation of fibroblast growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8CFG0

P

occurs_in:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF1

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8CFG0

P

occurs_in:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF1

involved_in

GO:0032836: glomerular basement membrane development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8CFG0

P

Seeded From UniProt

complete

MOUSE:SULF2

involved_in

GO:0040037: negative regulation of fibroblast growth factor receptor signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8K007

P

occurs_in:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF2

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF2

involved_in

GO:0032836: glomerular basement membrane development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8K007

P

Seeded From UniProt

complete

MOUSE:SULF2

involved_in

GO:0010575: positive regulation of vascular endothelial growth factor production

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8K007

P

occurs_in:(CL:0000653)

Seeded From UniProt

complete

MOUSE:SULF2

involved_in

GO:0003094: glomerular filtration

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q8K007

P

Seeded From UniProt

complete

MOUSE:WT1

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_regulation_target:(UniProtKB:Q8K007)
  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:WT1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:Q8K007)

Seeded From UniProt

complete


See also

References

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