Soluble FLT1 Binds Lipid Microdomains in Podocytes to Control Cell Morphology and Glomerular Barrier Function
2012; Cell Press; Volume: 151; Issue: 2 Linguagem: Inglês
10.1016/j.cell.2012.08.037
ISSN1097-4172
AutoresJing 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, András Nagy, Hans-Peter Gerber, Napoleone Ferrara, Tony Pawson, Susan E. Quaggin,
Tópico(s)Chronic Kidney Disease and Diabetes
ResumoSummaryVascular 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.Graphical abstractGraphical AbstractHighlights► VEGF receptor Flt1 regulates vasculature by modulating pericyte behavior ► sFLT1 promotes attachment and reorganization of the actin cytoskeleton of podocytes ► sFLT1 binds to the cell surface ganglioside GM3, triggering intracellular signaling ► Syndecan and nephrin phosphorylation are intracellular signals activated by sFLT1
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