TY - JOUR
T1 - Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function
AU - Jin, Jing
AU - Sison, Karen
AU - Li, Chengjin
AU - Tian, Ruijun
AU - Wnuk, Monika
AU - Sung, Hoon Ki
AU - Jeansson, Marie
AU - Zhang, Cunjie
AU - Tucholska, Monika
AU - Jones, Nina
AU - Kerjaschki, Dontscho
AU - Shibuya, Masabumi
AU - Fantus, I. George
AU - Nagy, Andras
AU - Gerber, Hans Peter
AU - Ferrara, Napoleone
AU - Pawson, Tony
AU - Quaggin, Susan E.
N1 - Funding Information:
We thank Doug Holmyard and Ken Harpal for EM and histology; Sarang Kulkarni, Steffen Lawo, and Laurence Pelletier for microscopy and imaging; Gerry Gish for peptide synthesis and lipid assays; Rick Bagshaw for mass spec advice and providing Lys-N enzyme; Moin Saleem for human podocyte cells; Jim Dennis, Andras Kapus, Johan van der Vlag, Roy Zent, Jin Gyoon Park, and Sergio Grinstein for helpful discussions; and Vivian Nguyen, Bret Larsen, and Lorne Taylor for technical assistance. This work was funded by CIHR grant MOP62931, TF grant 016002 to S.E.Q., who holds the Gabor-Zellerman Chair, CIHR-MOP57793 and HFSP-RGP0039/2009-C grants to T.P., CIHR- MOP-49409 to I.G.F., and TF grant 016002, CCRI grant 2010-700465 to A.N. J.J. received a CIHR Postdoctoral Fellowship, N.J. received a KRESCENT Award, and M.W. a Swiss NSF Postdoctoral Grant.
PY - 2012/10/12
Y1 - 2012/10/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2012.08.037
DO - 10.1016/j.cell.2012.08.037
M3 - Article
C2 - 23063127
AN - SCOPUS:84867519785
SN - 0092-8674
VL - 151
SP - 384
EP - 399
JO - Cell
JF - Cell
IS - 2
ER -