Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function

Jing Jin, Karen Sison, Chengjin Li, Ruijun Tian, Monika Wnuk, Hoon Ki Sung, Marie Jeansson, Cunjie Zhang, Monika Tucholska, Nina Jones, Dontscho Kerjaschki, Masabumi Shibuya, I. George Fantus, Andras Nagy, Hans Peter Gerber, Napoleone Ferrara, Tony Pawson, Susan E. Quaggin*

*Corresponding author for this work

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Vascular endothelial growth factor and its receptors, FLK1/KDR and FLT1, are key regulators of angiogenesis. Unlike FLK1/KDR, the role of FLT1 has remained elusive. FLT1 is produced as soluble (sFLT1) and full-length isoforms. Here, we show that pericytes from multiple tissues produce sFLT1. To define the biologic role of sFLT1, we chose the glomerular microvasculature as a model system. Deletion of Flt1 from specialized glomerular pericytes, known as podocytes, causes reorganization of their cytoskeleton with massive proteinuria and kidney failure, characteristic features of nephrotic syndrome in humans. The kinase-deficient allele of Flt1 rescues this phenotype, demonstrating dispensability of the full-length isoform. Using cell imaging, proteomics, and lipidomics, we show that sFLT1 binds to the glycosphingolipid GM3 in lipid rafts on the surface of podocytes, promoting adhesion and rapid actin reorganization. sFLT1 also regulates pericyte function in vessels outside of the kidney. Our findings demonstrate an autocrine function for sFLT1 to control pericyte behavior.

Original languageEnglish (US)
Pages (from-to)384-399
Number of pages16
JournalCell
Volume151
Issue number2
DOIs
StatePublished - Oct 12 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Jin, J., Sison, K., Li, C., Tian, R., Wnuk, M., Sung, H. K., Jeansson, M., Zhang, C., Tucholska, M., Jones, N., Kerjaschki, D., Shibuya, M., Fantus, I. G., Nagy, A., Gerber, H. P., Ferrara, N., Pawson, T., & Quaggin, S. E. (2012). Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell, 151(2), 384-399. https://doi.org/10.1016/j.cell.2012.08.037