Injury‐induced NF‐κB activation in the hippocampus: implications for neuronal survival

Kassed, Cheryl A.; Butler, Tanya L.; Patton, Geoffrey W.; Demesquita, D D; Navidomskis, M T; Mémet, Sylvie; Israël, Alain; Pennypacker, Keith R.

doi:10.1096/fj.03-0773fje

Cited by 53 publications

(26 citation statements)

References 113 publications

(94 reference statements)

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“…In line with our findings, the ␥ subunit was identified recently by DNA microarray analysis in the mouse hippocampus after chemical injury induced with trimethyltin, the drug causing mitochondrial dysfunction (59). Although no information is available about which splice form of ␥ was expressed, we hypothesize that induction of ␥a and the subsequent inhibition of the Na,K-ATPase activity might favor neuronal cell survival during energy deficiency and would be adaptive to sustain apoptotic insult.…”

Section: Discussionsupporting

confidence: 89%

Stress-induced Expression of the γ Subunit (FXYD2) Modulates Na,K-ATPase Activity and Cell Growth

Wetzel

Pascoa

Arystarkhova

2004

Journal of Biological Chemistry

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In kidney, the Na,K-ATPase is associated with a single span protein, the ␥ subunit (FXYD2). Two splice variants are differentially expressed along the nephron and have a differential influence on Na,K-ATPase when stably expressed in mammalian cells in culture. Here we used a combination of gene induction and gene silencing techniques to test the functional impact of ␥ by means other than transfection. NRK-52E cells (of proximal tubule origin) do not express ␥ as a protein under regular tissue culture conditions. However, when they were exposed to hyperosmotic medium, induction of only the ␥a splice variant was observed, which was accompanied by a reduction in the rate of cell division. Kinetic analysis of stable enzyme properties from control (␣1␤1) and hypertonicity-treated cultures (␣1␤1␥a) revealed a significant reduction (up to 60%) of Na,K-ATPase activity measured under V max conditions with little or no change in the amounts of ␣1␤1. This effect as well as the reduction in cell growth rate was practically abolished when ␥ expression was knocked down using specific small interfering RNA duplexes. Surprisingly, a similar induction of endogenous ␥a because of hypertonicity was seen in rat cell lines of other than renal origin: C6 (glioma), PC12 (pheochromocytoma), and L6 (myoblasts). Furthermore, exposure of NRK-52E cells to other stress inducers such as heat shock, exogenous oxidation, and chemical stress also resulted in a selective induction of ␥a. Taken together, the data imply that induction of ␥a may have adaptive value by being a part of a general cellular response to genotoxic stress.

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Section: Discussionsupporting

confidence: 89%

Stress-induced Expression of the γ Subunit (FXYD2) Modulates Na,K-ATPase Activity and Cell Growth

Wetzel

Pascoa

Arystarkhova

2004

Journal of Biological Chemistry

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“…Regulation by NF-B could also be indirect. NF-B complexes are involved in the control of a number of cellular responses during inflammatory and degenerative responses, and NF-B signaling regulates the transcription of a variety of genes that play potential roles in inflammatory reactions and neuronal survival after injury (19,(47)(48)(49). We further showed that inhibition of NF-B activation resulted in a significant reduction (ϳ50%) of CCL2 gene expression in lesion-reactive hippocampi.…”

Section: Discussionmentioning

confidence: 82%

NF-κB-Driven STAT2 and CCL2 Expression in Astrocytes in Response to Brain Injury

Khorooshi

Babcock

Owens

2008

The Journal of Immunology

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Tissue response to injury includes expression of genes encoding cytokines and chemokines. These regulate entry of immune cells to the injured tissue. The synthesis of many cytokines and chemokines involves NF-κB and signal transducers and activators of transcription (STAT). Injury to the CNS induces glial response. Astrocytes are the major glial population in the CNS. We examined expression of STATs and the chemokine CCL2 and their relationship to astroglial NF-κB signaling in the CNS following axonal transection. Double labeling with Mac-1/CD11b and glial fibrillary acidic protein revealed that STAT2 up-regulation and phosphorylation colocalized exclusively to astrocytes, suggesting the involvement of STAT2 activating signals selectively in astroglial response to injury. STAT1 was also up-regulated and phosphorylated but not exclusively in astrocytes. Both STAT2 up-regulation and phosphorylation were NF-κB -dependent since they did not occur in the lesion-reactive hippocampus of transgenic mice with specific inhibition of NF-κB activation in astrocytes. We further showed that lack of NF-κB signaling significantly reduced injury-induced CCL2 expression as well as leukocyte infiltration. Our results suggest that NF-κB signaling in astrocytes controls expression of both STAT2 and CCL2, and thus regulates infiltration of leukocytes into lesion-reactive hippocampus after axonal injury. Taken together, these findings indicate a central role for astrocytes in directing immune-glial interaction in the CNS injury response.

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“…Finally, FXYD2a but not FXYD2b expression is induced in renal cells of proximal origin as well as in several cell lines of other than renal origin by hypertonicity, heat shock, and chemical stress (98). Moreover, injury-induced NF-B activation induces FXYD2 expression in the hippocampus (48). FXYD2a induction in cells of renal origin is accompanied by a reduction in Na-K-ATPase activity and in the rate of cell division (98).…”

Section: F244mentioning

confidence: 99%

FXYD proteins: new regulators of Na-K-ATPase

Geering¹

2006

American Journal of Physiology-Renal Physiology

327

308

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FXYD proteins belong to a family of small-membrane proteins. Recent experimental evidence suggests that at least five of the seven members of this family, FXYD1 (phospholemman), FXYD2 (gamma-subunit of Na-K-ATPase), FXYD3 (Mat-8), FXYD4 (CHIF), and FXYD7, are auxiliary subunits of Na-K-ATPase and regulate Na-K-ATPase activity in a tissue- and isoform-specific way. These results highlight the complexity of the regulation of Na+ and K+ handling by Na-K-ATPase, which is necessary to ensure appropriate tissue functions such as renal Na+ reabsorption, muscle contractility, and neuronal excitability. Moreover, a mutation in FXYD2 has been linked to cases of human hypomagnesemia, indicating that perturbations in the regulation of Na-K-ATPase by FXYD proteins may be critically involved in pathophysiological states. A better understanding of this novel regulatory mechanism of Na-K-ATPase should help in learning more about its role in pathophysiological states. This review summarizes the present knowledge of the role of FXYD proteins in the modulation of Na-K-ATPase as well as of other proteins, their regulation, and their structure-function relationship.

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Injury‐induced NF‐κB activation in the hippocampus: implications for neuronal survival

Cited by 53 publications

References 113 publications

Stress-induced Expression of the γ Subunit (FXYD2) Modulates Na,K-ATPase Activity and Cell Growth

Stress-induced Expression of the γ Subunit (FXYD2) Modulates Na,K-ATPase Activity and Cell Growth

NF-κB-Driven STAT2 and CCL2 Expression in Astrocytes in Response to Brain Injury

FXYD proteins: new regulators of Na-K-ATPase

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