Oncotarget

Research Papers: Pathology:

Valproate hampers podocyte acquisition of immune phenotypes via intercepting the GSK3β facilitated NFkB activation

Pei Wang, Sijie Zhou, Yan Ge, Minglei Lu, Zhangsuo Liu _ and Rujun Gong

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Oncotarget. 2017; 8:88332-88344. https://doi.org/10.18632/oncotarget.19917

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Abstract

Pei Wang1,2, Sijie Zhou1,2, Yan Ge2, Minglei Lu1,2, Zhangsuo Liu1 and Rujun Gong1,2

1 Institute of Nephrology, Blood Purification Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

2 Department of Medicine, Division of Kidney Disease and Hypertension, Brown University School of Medicine, Providence, Rhode Island, USA

Correspondence to:

Zhangsuo Liu, email:

Rujun Gong, email:

Keywords: glomerulus, podocyte, immune phenotype, proteinuria, NFkB, Pathology Section

Received: July 02, 2017 Accepted: July 26, 2017 Published: August 03, 2017

Abstract

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) 3β overactivity, marked by a diminished inhibitory phosphorylation of GSK3β. In contrast, valproate, an anticonvulsant and mood stabilizer, offset GSK3β 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 GSK3β, suggesting an essential role of inhibitory phosphorylation of GSK3β. In vivo in LPS-injured mice, valproate therapy abolished GSK3β 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 GSK3β facilitated NFkB activation.


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