Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function.
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.
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Jing
J
Jin
Karen
K
Sison
Chengjin
C
Li
Ruijun
R
Tian
Monika
M
Wnuk
Hoon-Ki
HK
Sung
Marie
M
Jeansson
Cunjie
C
Zhang
Monika
M
Tucholska
Nina
N
Jones
Dontscho
D
Kerjaschki
Masabumi
M
Shibuya
I George
IG
Fantus
Andras
A
Nagy
Hans-Peter
HP
Gerber
Napoleone
N
Ferrara
Tony
T
Pawson
Susan E
SE
Quaggin
D000818:Animals; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000166:cytology* / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D020286:Pericytes / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000378:metabolism; D015398:Signal Transduction; D053667:Syndecans / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
D005732:Gangliosides; D008055:Lipids; D053667:Syndecans; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1