Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier

• Published in: International journal of molecular sciences 2019-11, Vol.20 (23), p.6010
• Main Authors: Branca, Jacopo Junio Valerio, Maresca, Mario, Morucci, Gabriele, Mello, Tommaso, Becatti, Matteo, Pazzagli, Luigia, Colzi, Ilaria, Gonnelli, Cristina, Carrino, Donatello, Paternostro, Ferdinando, Nicoletti, Claudio, Ghelardini, Carla, Gulisano, Massimo, Di Cesare Mannelli, Lorenzo, Pacini, Alessandra
• Format: Article
• Language: English
• Subjects: Actin; Actins - metabolism; Alzheimer's disease; Angiogenesis; Animals; Apoptosis; Blood-brain barrier; Blood-Brain Barrier - cytology; Blood-Brain Barrier - metabolism; Brain; Cadmium; Cadmium - metabolism; Cadmium chloride; Caspase-3; Cell Line; Central nervous system; Cigarette smoking; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelium; Food contamination & poisoning; Investigations; Nervous system; Neurodegeneration; Neurological diseases; Neurotoxicity; Permeability; Pollutants; Proteins; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal transduction; Tight Junctions - metabolism; Toxicity; Vimentin; Vimentin - metabolism; Zonula occludens-1 protein; Zonula Occludens-1 Protein - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20236010

Cadmium (Cd) is a highly toxic environmental pollutant released from the smelting and refining of metals and cigarette smoking. Oral exposure to cadmium may result in adverse effects on a number of tissues, including the central nervous system (CNS). In fact, its toxicity has been related to neurological disorders, as well as neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Under normal conditions, Cd barely reaches the brain in adults because of the presence of the blood-brain barrier (BBB); however, it has been demonstrated that Cd-dependent BBB alteration contributes to pathogenesis of neurodegeneration. However, the mechanism underlying Cd-dependent BBB alteration remain obscure. Here, we investigated the signaling pathway of Cd-induced tight junction (TJ), F-actin, and vimentin protein disassembly in a rat brain endothelial cell line (RBE4). RBE4 cells treated with 10 μM cadmium chloride (CdCl ) showed a dose- and time-dependent significant increase in reactive oxygen species (ROS) production. This phenomenon was coincident with the alteration of the TJ zonula occludens-1 (ZO-1), F-actin, and vimentin proteins. The Cd-dependent ROS increase elicited the upregulation of GRP78 expression levels, a chaperone involved in endoplasmic reticulum (ER) stress that induces caspase-3 activation. Further signal profiling by the pannexin-1 (PANX1) specific inhibitor Panx revealed a PANX1-independent increase in ATP spillage in Cd-treated endothelial cells. Our results point out that a ROS-dependent ER stress-mediated signaling pathway involving caspase-3 activation and ATP release is behind the BBB morphological alterations induced by Cd.