Fine-tuning of NF?B by glycogen synthase kinase 3? directs the fate of glomerular podocytes upon injury.

ABSTRACT: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B) is regulated by a myriad of signaling cascades including glycogen synthase kinase (GSK) 3? and plays a Janus role in podocyte injury. In vitro, lipopolysaccharide (LPS) or adriamycin (ADR) elicited podocyte injury and cytoskeletal disruption, associated with NF?B activation and induced expression of NF?B target molecules, including pro-survival Bcl-xL and podocytopathic mediators like MCP-1, cathepsin L, and B7-1. Broad-range inhibition of NF?B diminished the expression of all NF?B target genes, restored cytoskeleton integrity, but potentiated apoptosis. In contrast, blockade of GSK3? by lithium or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) mitigated the expression of podocytopathic mediators, ameliorated podocyte injury, but barely affected Bcl-xL expression or sensitized apoptosis. Mechanistically, GSK3? was sufficient and essential for RelA/p65 phosphorylation, specifically at serine 467, which specifies the expression of selective NF?B target molecules, including podocytopathic mediators, but not Bcl-xL. In vivo, lithium or TDZD-8 therapy improved podocyte injury and proteinuria in mice treated with LPS or ADR, concomitant with the suppression of podocytopathic mediators, but retained Bcl-xL in glomerulus. Broad-range inhibition of NF?B conferred similar but much weakened antiproteinuric and podoprotective effects accompanied with a blunted glomerular expression of Bcl-xL and marked podocyte apoptosis. Thus, the GSK3?-dictated fine-tuning of NF?B may serve as a novel therapeutic target for podocytopathy.

SUBMITTER: Bao H 

PROVIDER: S-EPMC4449834 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature