Journal
ONCOTARGET
Volume 8, Issue 51, Pages 88332-88344Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.19917
Keywords
glomerulus; podocyte; immune phenotype; proteinuria; NFkB; Pathology Section
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Funding
- key program of Joint Funds of the National Natural Science Foundation of China [U1604284]
- National key R&D program of China [2016YFC1305404]
- Natural Science Foundation of China [81670663]
- Medical Science and Technology Foundation of Henan Province [201601002]
- Foundation for Health
- U.S. National Institutes of Health [DK092485]
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Glomerular podocytes are able to transdifferentiate under disease conditions, acquire de novo immune phenotypes and behave as immunocompetent cells, like phagocytes or antigen-presenting cells. Upon stimulation with lipopolysaccharide (LPS), a prototypical pathogen-associated molecular pattern, podocytes demonstrated de novo expression of a variety of NFkB-dependent immune molecules that are pivotal for immune response, including major histocompatibility complex (MHC) class II, costimulatory molecule CD80, lysosomal protease cathepsin L as well as CC chemokine ligand 2 and 5, ultimately resulting in podocyte dysfunction, characterized by cellular shrinkage, a spindle-like or asterlike cell shape and impairment of actin cytoskeleton integrity. The LPS-elicited podocyte phenotypic changes were concurrent with nuclear factor (NF) kB phosphorylation, which was associated with glycogen synthase kinase (GSK) 3 beta overactivity, marked by a diminished inhibitory phosphorylation of GSK3 beta. In contrast, valproate, an anticonvulsant and mood stabilizer, offset GSK3 beta overactivity in LPS-injured podocytes and mitigated NFkB activation and podocyte acquisition of immune phenotypes as well as the ensuing cytopathic changes, podocyte cytoskeleton disorganization and dysfunction. The protective effect of valproate was strikingly blunted in podocytes expressing the constitutively active GSK3 beta, suggesting an essential role of inhibitory phosphorylation of GSK3 beta. In vivo in LPS-injured mice, valproate therapy abolished GSK3 beta overactivity in glomeruli and attenuated podocyte injury and albuminuria, concomitant with a lessened NFkB activation and diminished induction of diverse podocytopathic immune molecules in podocytes and glomeruli. Taken together, valproate directly protects against podocyte injury and hampers podocyte acquisition of de novo immune phenotypes via intercepting the GSK3 beta facilitated NFkB activation.
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