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

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

doi:10.18632/oncotarget.19917

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.

Highlights

As a key structural component of the glomerular filtration barrier, glomerular podocytes play a critical role in maintaining the homeostasis of glomerular filtration rate and glomerular permselectivity [1,2,3]
Multiple immune cell surface marker proteins that are pivotal for mediating cell-mediated immune response, such as major histocompatibility complex (MHC) class II [8], dendritic cell-specific intercellular adhesion molecule-3grabbing non-integrin [9], and the costimulatory molecule CD80 [11], have been shown in diseased podocytes
Valproate attenuates podocyte shape changes and actin cytoskeleton disorganization associated with LPS-induced acquisition of de novo immune phenotypes

Summary

Introduction

As a key structural component of the glomerular filtration barrier, glomerular podocytes play a critical role in maintaining the homeostasis of glomerular filtration rate and glomerular permselectivity [1,2,3]. A growing body of evidence suggests that podocytes, upon injury, may transdifferentiate and acquire de novo immune celllike phenotypes [5,6,7,8,9,10,11,12,13,14]. The exact role of these newly acquired immune phenotypes in the pathogenesis of podocyte or glomerular injury remains unclear. The NFkBdriven expression of numerous NFkB-dependent immune molecules is finely regulated by glycogen synthase kinase (GSK)3β [21, 22], which is a well-conserved, ubiquitous serine/threonine protein kinase originally characterized as one that regulates glucose metabolism [23] but lately implicated as an indispensable element for NFkB activation and proinflammatory responses [21, 24]. GSK3β may serve as a potential target for treating podocyte injury and glomerular disease

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Results

Conclusion