Article ; Online: N-sulfation of heparan sulfate is critical for syndecan-4-mediated podocyte cell-matrix interactions.
American journal of physiology. Renal physiology
2016 Volume 310, Issue 10, Page(s) F1123–35
Abstract: Previous research has shown that podocytes unable to assemble heparan sulfate on cell surface proteoglycan core proteins have compromised cell-matrix interactions. This report further explores the role of N-sulfation of intact heparan chains in podocyte- ... ...
| Abstract | Previous research has shown that podocytes unable to assemble heparan sulfate on cell surface proteoglycan core proteins have compromised cell-matrix interactions. This report further explores the role of N-sulfation of intact heparan chains in podocyte-matrix interactions. For the purposes of this study, a murine model in which the enzyme N-deacetylase/N-sulfotransferase 1 (NDST1) was specifically deleted in podocytes and immortalized podocyte cell lines lacking NDST1 were developed and used to explore the effects of such a mutation on podocyte behavior in vitro. NDST1 is a bifunctional enzyme, ultimately responsible for N-sulfation of heparan glycosaminoglycans produced by cells. Immunostaining of glomeruli from mice whose podocytes were null for Ndst1 (Ndst1(-/-)) showed a disrupted pattern of localization for the cell surface proteoglycan, syndecan-4, and for α-actinin-4 compared with controls. The pattern of immunostaining for synaptopodin and nephrin did not show as significant alterations. In vitro studies showed that Ndst1(-/-) podocytes attached, spread, and migrated less efficiently than Ndst1(+/+) podocytes. Immunostaining in vitro for several markers for molecules involved in cell-matrix interactions showed that Ndst1(-/-) cells had decreased clustering of syndecan-4 and decreased recruitment of protein kinase-Cα, α-actinin-4, vinculin, and phospho-focal adhesion kinase to focal adhesions. Total intracellular phospho-focal adhesion kinase was decreased in Ndst1(-/-) compared with Ndst1(+/+) cells. A significant decrease in the abundance of activated integrin α5β1 on the cell surface of Ndst1(-/-) cells compared with Ndst1(+/+) cells was observed. These results serve to highlight the critical role of heparan sulfate N-sulfation in facilitating normal podocyte-matrix interactions. |
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| MeSH term(s) | Actinin/metabolism ; Animals ; Cell Adhesion ; Cell Movement ; Cells, Cultured ; Cytoskeleton/metabolism ; Disease Models, Animal ; Extracellular Matrix/metabolism ; Focal Adhesions/metabolism ; Glomerular Basement Membrane/metabolism ; Heparitin Sulfate/metabolism ; Integrin alpha5beta1/metabolism ; Mice ; Mice, Transgenic ; Podocytes/metabolism ; Sulfotransferases/genetics ; Syndecan-4/metabolism |
| Chemical Substances | Actn4 protein, mouse ; Integrin alpha5beta1 ; Sdc4 protein, mouse ; Syndecan-4 ; Actinin (11003-00-2) ; Heparitin Sulfate (9050-30-0) ; Sulfotransferases (EC 2.8.2.-) ; heparitin sulfotransferase (EC 2.8.2.8) |
| Language | English |
| Publishing date | 2016-03-02 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 603837-2 |
| ISSN | 1522-1466 ; 0363-6127 |
| ISSN (online) | 1522-1466 |
| ISSN | 0363-6127 |
| DOI | 10.1152/ajprenal.00603.2015 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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