Inhibition of podocyte FAK protects against proteinuria and foot process effacement.
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that plays a critical role in cell motility. Movement and retraction of podocyte foot processes, which accompany podocyte injury, suggest focal adhesion disassembly. To understand better the mechanisms by which podocyte foot process effacement leads to proteinuria and kidney failure, we studied the function of FAK in podocytes. In murine models, glomerular injury led to activation of podocyte FAK, followed by proteinuria and foot process effacement. Both podocyte-specific deletion of FAK and pharmacologic inactivation of FAK abrogated the proteinuria and foot process effacement induced by glomerular injury. In vitro, podocytes isolated from conditional FAK knockout mice demonstrated reduced spreading and migration; pharmacologic inactivation of FAK had similar effects on wild-type podocytes. In conclusion, FAK activation regulates podocyte foot process effacement, suggesting that pharmacologic inhibition of this signaling cascade may have therapeutic potential in the setting of glomerular injury.
Departments of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Hong
H
Ma
Akashi
A
Togawa
Keita
K
Soda
Junhui
J
Zhang
Sik
S
Lee
Ming
M
Ma
Zhiheng
Z
Yu
Thomas
T
Ardito
Jan
J
Czyzyk
Lonnette
L
Diggs
Dominique
D
Joly
Shinji
S
Hatakeyama
Eiji
E
Kawahara
Lawrence
L
Holzman
Jun Lin
JL
Guan
Shuta
S
Ishibe
D000199:Actins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D017353:Gene Deletion; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011743:Pyrimidines / Q000494:pharmacology
D000199:Actins; D004791:Enzyme Inhibitors; C516714:NVP-TAE684; D011743:Pyrimidines; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020778:Matrix Metalloproteinase 2