| First Author | Xu W | Year | 2014 |
| Journal | Am J Pathol | Volume | 184 |
| Issue | 10 | Pages | 2742-56 |
| PubMed ID | 25239564 | Mgi Jnum | J:216354 |
| Mgi Id | MGI:5608708 | Doi | 10.1016/j.ajpath.2014.06.027 |
| Citation | Xu W, et al. (2014) Glycogen synthase kinase 3beta 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 |
| abstractText | 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 3beta (GSK3beta), a multitasking kinase lately identified as a mediator of kidney injury. However, the role of GSK3beta in podocytopathy remains obscure. In doxorubicin (Adriamycin)-injured podocytes, lithium, a GSK3beta 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 GSK3beta 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 GSK3beta highly mimicked, whereas ectopic expression of a constitutively active GSK3beta 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 GSK3beta. Furthermore, paxillin interacted with GSK3beta and served as its substrate. In mice with doxorubicin nephropathy, a single low dose of lithium ameliorated proteinuria and glomerulosclerosis. Consistently, lithium therapy abrogated GSK3beta overactivity, blunted paxillin hyperphosphorylation, and reinstated actin cytoskeleton integrity in glomeruli associated with an early attenuation of podocyte foot process effacement. Thus, GSK3beta-modulated focal adhesion dynamics might serve as a novel therapeutic target for podocytopathy. |
