Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm

被引:138
作者
Simons, M
Schwarz, K
Kriz, W
Miettinen, A
Reiser, J
Mundel, P
Holthöfer, H
机构
[1] Univ Helsinki, Dept Bacteriol & Immunol, FIN-00014 Helsinki, Finland
[2] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA
[3] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10467 USA
[4] Heidelberg Univ, Dept Anat & Cell Biol, Heidelberg, Germany
关键词
D O I
10.1016/S0002-9440(10)61782-8
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
NPHS1 has recently been identified as the gene whose muta ions cause congenital nephrotic syndrome of the Finnish type. The respective gene product nephrin is a transmembrane protein expressed in glomerular podocytes and primarily localized to the glomerular slit diaphragm. This interpodocyte junction functions in the glomerular filtration by restricting the passage of plasma proteins into the urinary space in a size-selective manner. The functional role of nephrin in this filtration process is so far not very well understood. in this study, we show that nephrin associates in an oligomerized form with signaling microdomains, also known as lipid rafts, and that these localize to the slit diaphragm. We also show that the nephrin-containing rafts can be immunoisolated with the 27A antibody recognizing a podocyte-specific 9-O-acetylated GD3 ganglioside. in a previous study it has been shown that the in vivo injection of this antibody leads to morphological changes of the filtration slits resembling foot process effacement. Here, we report that, in this model of foot process effacement, nephrin dislocates to the apical pole of the narrowed filtration slits and also that it is tyrosine phosphorylated. We suggest that lipid rafts are important in the spatial organization of the glomerular slit diaphragm under physiological and pathological conditions.
引用
收藏
页码:1069 / 1077
页数:9
相关论文
共 42 条
[1]   Cloning and expression of the rat nephrin homolog [J].
Ahola, H ;
Wang, SX ;
Luimula, P ;
Solin, ML ;
Holzman, LB ;
Holthöfer, H .
AMERICAN JOURNAL OF PATHOLOGY, 1999, 155 (03) :907-913
[2]   NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome [J].
Boute, N ;
Gribouval, O ;
Roselli, S ;
Benessy, F ;
Lee, H ;
Fuchshuber, A ;
Dahan, K ;
Gubler, MC ;
Niaudet, P ;
Antignac, C .
NATURE GENETICS, 2000, 24 (04) :349-354
[3]   Functions of lipid rafts in biological membranes [J].
Brown, DA ;
London, E .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1998, 14 :111-136
[4]   EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains [J].
Brückner, K ;
Labrador, JP ;
Scheiffele, P ;
Herb, A ;
Seeburg, PH ;
Klein, R .
NEURON, 1999, 22 (03) :511-524
[5]  
CAULFIELD JP, 1976, LAB INVEST, V34, P43
[6]   GLOMERULAR-PERMEABILITY BARRIER IN THE RAT - FUNCTIONAL ASSESSMENT BY IN-VITRO METHODS [J].
DANIELS, BS ;
DEEN, WM ;
MAYER, G ;
MEYER, T ;
HOSTETTER, TH .
JOURNAL OF CLINICAL INVESTIGATION, 1993, 92 (02) :929-936
[7]  
DEKAN G, 1990, AM J PATHOL, V137, P913
[8]   STRUCTURAL DETERMINANTS OF GLOMERULAR HYDRAULIC PERMEABILITY [J].
DRUMOND, MC ;
DEEN, WM .
AMERICAN JOURNAL OF PHYSIOLOGY, 1994, 266 (01) :F1-+
[9]   Lipid domain structure of the plasma membrane revealed by patching of membrane components [J].
Harder, T ;
Scheiffele, P ;
Verkade, P ;
Simons, K .
JOURNAL OF CELL BIOLOGY, 1998, 141 (04) :929-942
[10]   Nephrin localizes at the podocyte filtration slit area and is characteristically spliced in the human kidney [J].
Holthöfer, H ;
Ahola, H ;
Solin, ML ;
Wang, SX ;
Palmen, T ;
Luimula, P ;
Miettinen, A ;
Kerjaschki, D .
AMERICAN JOURNAL OF PATHOLOGY, 1999, 155 (05) :1681-1687