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

86 Citations (Scopus)

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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Podocytes
Pericytes
Lipids
Protein Isoforms
Glycosphingolipids
Vascular Endothelial Growth Factor Receptor
Behavior Control
Nephrotic Syndrome
Microvessels
Cytoskeleton
Proteinuria
Proteomics
Renal Insufficiency
Actins
Phosphotransferases
Adhesion
Alleles
Tissue
Phenotype
Kidney

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Jin, Jing ; Sison, Karen ; Li, Chengjin ; Tian, Ruijun ; Wnuk, Monika ; Sung, Hoon Ki ; Jeansson, Marie ; Zhang, Cunjie ; Tucholska, Monika ; Jones, Nina ; Kerjaschki, Dontscho ; Shibuya, Masabumi ; Fantus, I. George ; Nagy, Andras ; Gerber, Hans Peter ; Ferrara, Napoleone ; Pawson, Tony ; Quaggin, Susan E. / Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. In: Cell. 2012 ; Vol. 151, No. 2. pp. 384-399.
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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.",
author = "Jing Jin and Karen Sison and Chengjin Li and Ruijun Tian and Monika Wnuk and Sung, {Hoon Ki} and Marie Jeansson and Cunjie Zhang and Monika Tucholska and Nina Jones and Dontscho Kerjaschki and Masabumi Shibuya and Fantus, {I. George} and Andras Nagy and Gerber, {Hans Peter} and Napoleone Ferrara and Tony Pawson and Quaggin, {Susan E.}",
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Jin, J, Sison, K, Li, C, Tian, R, Wnuk, M, Sung, HK, Jeansson, M, Zhang, C, Tucholska, M, Jones, N, Kerjaschki, D, Shibuya, M, Fantus, IG, Nagy, A, Gerber, HP, Ferrara, N, Pawson, T & Quaggin, SE 2012, 'Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function', Cell, vol. 151, no. 2, pp. 384-399. https://doi.org/10.1016/j.cell.2012.08.037

Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. / Jin, Jing; Sison, Karen; Li, Chengjin; Tian, Ruijun; Wnuk, Monika; Sung, Hoon Ki; Jeansson, Marie; Zhang, Cunjie; Tucholska, Monika; Jones, Nina; Kerjaschki, Dontscho; Shibuya, Masabumi; Fantus, I. George; Nagy, Andras; Gerber, Hans Peter; Ferrara, Napoleone; Pawson, Tony; Quaggin, Susan E.

In: Cell, Vol. 151, No. 2, 12.10.2012, p. 384-399.

Research output: Contribution to journalArticle

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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.

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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