Albumin causes increased myosin light chain kinase expression in astrocytes via p38 mitogen-activated protein kinase

Janet L. Rossi, Hantamalala Ralay Ranaivo, Fatima Patel, Maryann Chrzaszcz, Charu Venkatesan, Mark S. Wainwright*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Myosin light chain kinase (MLCK) plays an important role in the reorganization of the cytoskeleton, leading to disruption of vascular barrier integrity in multiple organs, including the blood-brain barrier (BBB), after traumatic brain injury (TBI). MLCK has been linked to transforming growth factor (TGF) and rho kinase signaling pathways, but the mechanisms regulating MLCK expression following TBI are not well understood. Albumin leaks into the brain parenchyma following TBI, activates glia, and has been linked to TGF-β receptor signaling. We investigated the role of albumin in the increase of MLCK in astrocytes and the signaling pathways involved in this increase. After midline closed-skull TBI in mice, there was a significant increase in MLCK-immunoreactive (IR) cells and albumin extravasation, which was prevented by treatment with the MLCK inhibitor ML-7. Using immunohistochemical methods, we identified the MLCK-IR cells as astrocytes. In primary astrocytes, exposure to albumin increased both isoforms of MLCK, 130 and 210. Inhibition of the TGF-β receptor partially prevented the albumin-induced increase in both isoforms, which was not prevented by inhibition of smad3. Inhibition of p38 MAPK, but not ERK, JNK, or rho kinase, also prevented this increase. These results are further evidence of a role of MLCK in the mechanisms of BBB compromise following TBI and identify astrocytes as a cell type, in addition to endothelium in the BBB, that expresses MLCK. These findings implicate albumin, acting through p38 MAPK, in a novel mechanism by which activation of MLCK following TBI may lead to compromise of the BBB.

Original languageEnglish (US)
Pages (from-to)852-861
Number of pages10
JournalJournal of Neuroscience Research
Volume89
Issue number6
DOIs
StatePublished - Jun 2011

Keywords

  • Astrocyte
  • Blood-brain barrier
  • Myosin light chain kinase
  • Transforming growth factor
  • Traumatic brain injury

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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