Aquaporin-4 in manganese-treated cultured astrocytes

Kakulavarapu V Rama Rao, Arumugam R. Jayakumar, Pichili V B Reddy, Xiaoying Tong, Kevin M. Curtis, Michael D Norenberg

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Manganese in excess is neurotoxic and causes CNS injury resembling that of Parkinson's disease. In brain, astrocytes predominantly take up and accumulate manganese and are thus vulnerable to its toxicity. Manganese was shown to induce cell swelling in cultured astrocytes, and oxidative/ nitrosative stress (ONS) mediates such swelling. As aquaporin-4 (AQP4) is important in the mechanism of astrocyte swelling, we examined the effect of manganese on AQP4 protein levels in cultured astrocytes. Treatment of cultures with manganese increased AQP4 protein in the plasma membrane (PM), whereas total cellular AQP4 protein and mRNA levels were unchanged, suggesting that increased AQP4 levels is due to its increased stability and/or increased trafficking to the PM and not to its neosynthesis. AQP4 gene silencing by small interfering ribonucleic acid resulted in a marked reduction in astrocyte swelling by manganese. Antioxidants, as well as an inhibitor of nitric oxide synthase, diminished the increase in AQP4 protein expression, suggesting a role of ONS in the mechanism of AQP4 increase. As ONS is known to activate mitogen-activated protein kinases (MAPKs) and MAPK activation has been implicated in astrocyte swelling, we examined the effect of manganese on the activation of MAPKs and found an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, C-Jun amino-terminal kinase (JNK)1/2/3, and p38-MAPK. Inhibitors of ERK1/2 and p38-MAPK (but not of JNK) blocked (40-60%) the manganese-induced increase in AQP4 protein content and astrocyte swelling, suggesting the involvement of these kinases in the increased AQP4 content. Inhibition of oxidative stress or MAPKs may represent potential strategies for counteracting AQP4-related neurological complications associated with manganese toxicity.

Original languageEnglish
Pages (from-to)1490-1499
Number of pages10
JournalGLIA
Volume58
Issue number12
DOIs
StatePublished - Sep 1 2010

Fingerprint

Aquaporin 4
Manganese
Astrocytes
Mitogen-Activated Protein Kinases
Oxidative Stress
p38 Mitogen-Activated Protein Kinases
Phosphotransferases
Cell Membrane
MAP Kinase Kinase 4
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Gene Silencing
Nitric Oxide Synthase
Protein Kinases
Parkinson Disease

Keywords

  • Aquaporin-4
  • Astrocyte swelling
  • Astrocytes
  • Cell surface biotinylation
  • Manganese toxicity
  • Mitogen-activated protein kinases
  • Oxidative/nitrosative stress

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

Rao, K. V. R., Jayakumar, A. R., Reddy, P. V. B., Tong, X., Curtis, K. M., & Norenberg, M. D. (2010). Aquaporin-4 in manganese-treated cultured astrocytes. GLIA, 58(12), 1490-1499. https://doi.org/10.1002/glia.21023

Aquaporin-4 in manganese-treated cultured astrocytes. / Rao, Kakulavarapu V Rama; Jayakumar, Arumugam R.; Reddy, Pichili V B; Tong, Xiaoying; Curtis, Kevin M.; Norenberg, Michael D.

In: GLIA, Vol. 58, No. 12, 01.09.2010, p. 1490-1499.

Research output: Contribution to journalArticle

Rao, KVR, Jayakumar, AR, Reddy, PVB, Tong, X, Curtis, KM & Norenberg, MD 2010, 'Aquaporin-4 in manganese-treated cultured astrocytes', GLIA, vol. 58, no. 12, pp. 1490-1499. https://doi.org/10.1002/glia.21023
Rao KVR, Jayakumar AR, Reddy PVB, Tong X, Curtis KM, Norenberg MD. Aquaporin-4 in manganese-treated cultured astrocytes. GLIA. 2010 Sep 1;58(12):1490-1499. https://doi.org/10.1002/glia.21023
Rao, Kakulavarapu V Rama ; Jayakumar, Arumugam R. ; Reddy, Pichili V B ; Tong, Xiaoying ; Curtis, Kevin M. ; Norenberg, Michael D. / Aquaporin-4 in manganese-treated cultured astrocytes. In: GLIA. 2010 ; Vol. 58, No. 12. pp. 1490-1499.
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