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Article

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

by
Jacopo Junio Valerio Branca
1,*,
Mario Maresca
2,
Gabriele Morucci
1,
Tommaso Mello
3,
Matteo Becatti
3,
Luigia Pazzagli
3,
Ilaria Colzi
4,
Cristina Gonnelli
4,
Donatello Carrino
1,
Ferdinando Paternostro
1,
Claudio Nicoletti
1,
Carla Ghelardini
2,
Massimo Gulisano
1,
Lorenzo Di Cesare Mannelli
2 and
Alessandra Pacini
1,*
1
Department of Experimental and Clinical Medicine, Anatomy and Histology Section, University of Florence, 50134 Florence, Italy
2
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
3
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Florence, Italy
4
Department of Biology, Plant Ecology and Physiology Laboratory, University of Florence, 50121 Florence, Italy
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 6010; https://doi.org/10.3390/ijms20236010
Submission received: 3 November 2019 / Revised: 21 November 2019 / Accepted: 26 November 2019 / Published: 29 November 2019
(This article belongs to the Section Molecular Toxicology)
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Abstract

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 (CdCl2) 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 10Panx 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.
Keywords: cadmium; blood brain barrier; RBE4 cell line; ZO-1; ROS production; ER stress; caspase-3 activation; ATP extrusion cadmium; blood brain barrier; RBE4 cell line; ZO-1; ROS production; ER stress; caspase-3 activation; ATP extrusion
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MDPI and ACS Style

Branca, J.J.V.; Maresca, M.; Morucci, G.; Mello, T.; Becatti, M.; Pazzagli, L.; Colzi, I.; Gonnelli, C.; Carrino, D.; Paternostro, F.; et al. Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier. Int. J. Mol. Sci. 2019, 20, 6010. https://doi.org/10.3390/ijms20236010

AMA Style

Branca JJV, Maresca M, Morucci G, Mello T, Becatti M, Pazzagli L, Colzi I, Gonnelli C, Carrino D, Paternostro F, et al. Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier. International Journal of Molecular Sciences. 2019; 20(23):6010. https://doi.org/10.3390/ijms20236010

Chicago/Turabian Style

Branca, Jacopo Junio Valerio, Mario Maresca, Gabriele Morucci, Tommaso Mello, Matteo Becatti, Luigia Pazzagli, Ilaria Colzi, Cristina Gonnelli, Donatello Carrino, Ferdinando Paternostro, and et al. 2019. "Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier" International Journal of Molecular Sciences 20, no. 23: 6010. https://doi.org/10.3390/ijms20236010

APA Style

Branca, J. J. V., Maresca, M., Morucci, G., Mello, T., Becatti, M., Pazzagli, L., Colzi, I., Gonnelli, C., Carrino, D., Paternostro, F., Nicoletti, C., Ghelardini, C., Gulisano, M., Di Cesare Mannelli, L., & Pacini, A. (2019). Effects of Cadmium on ZO-1 Tight Junction Integrity of the Blood Brain Barrier. International Journal of Molecular Sciences, 20(23), 6010. https://doi.org/10.3390/ijms20236010

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