Fine-tuning of NFκB by glycogen synthase kinase 3β directs the fate of glomerular podocytes upon injury

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappa B) is regulated by a myriad of signaling cascades including glycogen synthase kinase (GSK) 3 beta and plays a Janus role in podocyte injury. In vitro, lipopolysaccharide (LPS) or adriamycin (ADR) elicited podocyte injury and cytoskeletal disruption, associated with NF kappa B activation and induced expression of NF kappa B target molecules, including pro-survival Bcl-xL and podocytopathic mediators like MCP-1, cathepsin L, and B7-1. Broad-range inhibition of NF kappa B diminished the expression of all NF kappa B target genes, restored cytoskeleton integrity, but potentiated apoptosis. In contrast, blockade of GSK3 beta by lithium or 4-benzyl-2-methy1-1,2,4-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 beta was sufficient and essential for RelA/p65 phosphorylation, specifically at serine 467, which specifies the expression of selective NF kappa 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 kappa 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 beta-dictated fine-tuning of NM may serve as a novel therapeutic target for podocytopathy.