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. (2012). Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell, 151(2), pp. 384-399. Cell Press 10.1016/j.cell.2012.08.037

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Wnuk, Monika

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0092-8674

Publisher:

Cell Press

Language:

English

Submitter:

Monika Wnuk

Date Deposited:

27 Jun 2014 08:31

Last Modified:

27 Jun 2014 08:31

Publisher DOI:

10.1016/j.cell.2012.08.037

PubMed ID:

23063127

URI:

https://boris.unibe.ch/id/eprint/54035

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