Glycogen synthase kinase 3ß dictates podocyte motility and focal adhesion turnover by modulating paxillin activity: implications for the protective effect of low-dose lithium in podocytopathy.
Am J Pathol
; 184(10): 2742-56, 2014 Oct.
Article
in En
| MEDLINE
| ID: mdl-25239564
ABSTRACT
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 3ß (GSK3ß), a multitasking kinase lately identified as a mediator of kidney injury. However, the role of GSK3ß in podocytopathy remains obscure. In doxorubicin (Adriamycin)-injured podocytes, lithium, a GSK3ß 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 GSK3ß 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 GSK3ß highly mimicked, whereas ectopic expression of a constitutively active GSK3ß 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 GSK3ß. Furthermore, paxillin interacted with GSK3ß and served as its substrate. In mice with doxorubicin nephropathy, a single low dose of lithium ameliorated proteinuria and glomerulosclerosis. Consistently, lithium therapy abrogated GSK3ß overactivity, blunted paxillin hyperphosphorylation, and reinstated actin cytoskeleton integrity in glomeruli associated with an early attenuation of podocyte foot process effacement. Thus, GSK3ß-modulated focal adhesion dynamics might serve as a novel therapeutic target for podocytopathy.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Focal Adhesions
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Glycogen Synthase Kinase 3
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Podocytes
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Paxillin
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Kidney Glomerulus
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Lithium
Limits:
Animals
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Humans
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Male
Language:
En
Journal:
Am J Pathol
Year:
2014
Document type:
Article