title: The podocyte protein nephrin is required for cardiac vessel formation.
abstract: Nephrin (NPHS1) has been described as an important structural protein of kidney podocytes. Mutations in this gene lead to the Finnish-type congenital nephrotic syndrome. More recently, a role of nephrin as a signalling molecule in kidney podocytes has been identified. Here, we show that nephrin not only has a function in kidney podocytes, but is also required for cardiovascular development. Nephrin is expressed in the epicardium and coronary vessels during human and mouse embryonic development. Nephrin knockout embryos showed abnormal epicardial cell morphology and, at later stages of development, a reduced number of coronary vessels due to increased apoptosis, and in addition, cardiac fibrosis. Connexin 43, which is required for coronary vessel formation, was downregulated in nephrin knockout embryos. Expression of the p75NTR neurotrophin receptor, a known mediator of apoptosis, was increased in mutants. Furthermore, co-immunoprecipitation studies demonstrated a direct interaction of nephrin with p75NTR. Primary nephrin-deficient cardiac cells showed a 5-fold higher rate of apoptosis in response to progenitor of nerve growth factor compared with wild-type cells, which could be rescued by RNAi against p75NTR. Taken together, our data demonstrate that nephrin directly interacts with p75NTR and reveal an important role for nephrin in murine cardiac development by permitting survival of cardiovascular progenitor cells.
authors.affiliation: LBPG CNRS/INSERM U998/UNSA, 06107 Nice, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wagner
authors.forename: Harris
authors.initials: H
authors.lastname: Morrison
authors.forename: Sophie
authors.initials: S
authors.lastname: Pagnotta
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Michiels
authors.forename: Yannick
authors.initials: Y
authors.lastname: Schwab
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedl
authors.forename: Kay-Dietrich
authors.initials: KD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D017209:Apoptosis; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D003331:Coronary Vessels / Q000196:embryology* / Q000378:metabolism; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D038081:Organogenesis / Q000235:genetics; D010496:Pericardium / Q000196:embryology* / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020798:Two-Hybrid System Techniques
chemical_list: D018031:Connexin 43; C543076:GJA1 protein, mouse; D008565:Membrane Proteins; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C113267:nephrin