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.