Podocyte migration during nephrotic syndrome requires a coordinated interplay between cathepsin L and alpha3 integrin.
Podocyte foot process effacement and disruption of the slit diaphragm are typically associated with glomerular proteinuria and can be induced in rats by the injection of puromycin aminonucleoside. Here, we show that the induction of puromycin aminonucleoside nephrosis involves podocyte migration conducted by a coordinated interplay between the cysteine protease cathepsin L and alpha(3) integrin. Puromycin aminonucleoside treatment up-regulates cathepsin L expression in podocytes in vivo as well as expression and enzymatic activity of cathepsin L in podocytes in vitro. Isolated podocytes from mice lacking cathepsin L are protected from cell puromycin aminonucleoside-induced cell detachment. The functional significance of cathepsin L expression was underscored by the observation that puromycin aminonucleoside-induced cell migration was slowed down in cathepsin L-deficient podocytes and by the preservation of cell-cell contacts and expression of vital slit diaphragm protein CD2AP. Cathepsin L expression and activity were induced in podocytes lacking alpha(3) integrin. Similarly, acute functional inhibition of alpha(3) integrin in wild type podocytes with a blocking antibody increased the expression of cathepsin L activity. Down-regulation of alpha(3) integrin protected against puromycin aminonucleoside-induced podocyte detachment. In summary, these data establish that podocyte foot process effacement is a migratory event involving a novel interplay between cathepsin L and alpha(3) integrin.
Reiser
Jochen
J
Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Oh
Jun
J
Shirato
Isao
I
Asanuma
Katsuhiko
K
Hug
Andreas
A
Mundel
Thomas M
TM
Honey
Karen
K
Ishidoh
Kazumi
K
Kominami
Eiki
E
Kreidberg
Jordan A
JA
Tomino
Yasuhiko
Y
Mundel
Peter
P
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D003598:Cytoskeletal Proteins; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D039422:Integrin alpha3 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009404:Nephrotic Syndrome / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism; D011691:Puromycin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D039422:Integrin alpha3; D016023:Integrins; D011506:Proteins; D011691:Puromycin; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C534280:Ctsl protein, rat