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2017 ; 8
(51
): 88332-88344
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Valproate hampers podocyte acquisition of immune phenotypes via intercepting the
GSK3? facilitated NFkB activation
#MMPMID29179438
Wang P
; Zhou S
; Ge Y
; Lu M
; Liu Z
; Gong R
Oncotarget
2017[Oct]; 8
(51
): 88332-88344
PMID29179438
show ga
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?
overactivity, marked by a diminished inhibitory phosphorylation of GSK3?. In
contrast, valproate, an anticonvulsant and mood stabilizer, offset GSK3?
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?, suggesting an essential role of inhibitory phosphorylation of
GSK3?. In vivo in LPS-injured mice, valproate therapy abolished GSK3?
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? facilitated
NFkB activation.