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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Pathol
2014 ; 184
(10
): 2742-56
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Glycogen synthase kinase 3? dictates podocyte motility and focal adhesion
turnover by modulating paxillin activity: implications for the protective effect
of low-dose lithium in podocytopathy
#MMPMID25239564
Xu W
; Ge Y
; Liu Z
; Gong R
Am J Pathol
2014[Oct]; 184
(10
): 2742-56
PMID25239564
show ga
Aberrant focal adhesion turnover is centrally involved in podocyte actin
cytoskeleton disorganization and foot process effacement. The structural and
dynamic integrity of focal adhesions is orchestrated by multiple cell signaling
molecules, including glycogen synthase kinase 3? (GSK3?), a multitasking kinase
lately identified as a mediator of kidney injury. However, the role of GSK3? in
podocytopathy remains obscure. In doxorubicin (Adriamycin)-injured podocytes,
lithium, a GSK3? inhibitor and neuroprotective mood stabilizer, obliterated the
accelerated focal adhesion turnover, rectified podocyte hypermotility, and
restored actin cytoskeleton integrity. Mechanistically, lithium counteracted the
doxorubicin-elicited GSK3? overactivity and the hyperphosphorylation and
overactivation of paxillin, a focal adhesion-associated adaptor protein.
Moreover, forced expression of a dominant negative kinase dead mutant of GSK3?
highly mimicked, whereas ectopic expression of a constitutively active GSK3?
mutant abolished, the effect of lithium in doxorubicin-injured podocytes,
suggesting that the effect of lithium is mediated, at least in part, through
inhibition of GSK3?. Furthermore, paxillin interacted with GSK3? and served as
its substrate. In mice with doxorubicin nephropathy, a single low dose of lithium
ameliorated proteinuria and glomerulosclerosis. Consistently, lithium therapy
abrogated GSK3? overactivity, blunted paxillin hyperphosphorylation, and
reinstated actin cytoskeleton integrity in glomeruli associated with an early
attenuation of podocyte foot process effacement. Thus, GSK3?-modulated focal
adhesion dynamics might serve as a novel therapeutic target for podocytopathy.