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Abstract: SA-PO234

The Loss of Heparin Sulphate Editing Enzyme Sulf1 Reduces VEGF Signaling and Enhances Endothelial Glomerular Injury and Albuminuria

Session Information

  • Glomerular: Cell Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology

Authors

  • Masseli, Anna Katharina, Hannover Medical School, Hannover, Germany
  • Schroder, Patricia Ann, Mount Desert Island Biological Laboratory, Salisbury Cove, Maine, United States
  • Beverly-Staggs, Laura L., Mount Desert Island Biological Lab, Salisbury Harbor, Maine, United States
  • Schiffer, Mario, Hannover Medical School, Hannover, Germany
  • Müller-Deile, Janina, MHH, Hanover, Germany
  • Schenk, Heiko Joachim, Hannover Medical School, Hannover, Germany
  • Park, Joon-Keun, Hannover Medical School, Hannover, Germany
  • Haller, Hermann G., Hannover Medical School, Hannover, Germany
Background

The endothelial cell surface is covered by the heparin sulphate proteoglycans (HSPG). Alterations in the level of 6-O-sulfation of the HS chains modulate the binding and release of signaling molecules and affect vascular function. The regulation of the glycocalyx is not well understood. Heparan sulfate 6-O-endosulfatases (sulf1 and -2) regulate the binding properties of the glycocalyx. We tested the hypothesis that 6-O-sulfation is important for glomerular stability and that changes in 6-O-sulfation lead to glomerular damage and albuminuria.

Methods

To assess sulf-1 and -2 function in vivo we used a transgenic zebrafish model (Tg(I-fabp:eGFP-DBP) and measured edema formation and loss of fluorescent protein from the circulation after knock-down of sulf-1 and -2. We further tested whether loss of sulf enhanced glomerular injury in zebrafish using PAN injury. In addition, mice deficient for Sulf-1 and -2 were analyzed. Urinary albumin was measured by ELISA. Immunohistochemistry was performed on cryostat or on paraffin sections.

Results

Loss of Sulf-1 and -2A/B led to a dose-dependent increase in edema formation and albuminuria in zebrafish. Vascular permeability was enhanced after sulf-2 knock down. Reduction of sulfatases enhanced the PAN-induced albuminuria significantly. Vascular patterning was slightly affected by Sulf-2, indicating a role in vascular development of the isoform. In Sulf-2 deficient mice albuminuria occurred after week 4. The glomerular mesangium showed increased proliferation. Glomerular VEGF165 as well as p38 and pERK immunoreactivity were increased.

Conclusion

The level of 6-O-sulfation of HS chains of the glycocalyx is an important determinator of glomerular health and pathophysiology. Our results suggest that Sulf-1 and -2 regulate the signaling properties of VEGF and other growth factors in the renal microcirculation.

Funding

  • Government Support - Non-U.S.