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

Jacopo Junio Valerio Branca,Ilaria Colzi,Lorenzo Di Cesare Mannelli,Matteo Becatti,Luigia Pazzagli,Tommaso Mello,Ferdinando Paternostro,Mario Maresca,Claudio Nicoletti,Donatello Carrino,Alessandra Pacini,Massimo Gulisano,Cristina Gonnelli,Gabriele Morucci,Carla Ghelardini

doi:10.3390/ijms20236010

Jacopo Junio Valerio Branca, Ilaria Colzi + Show 13 more

Open Access

https://doi.org/10.3390/ijms20236010

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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.

Highlights

Cadmium (Cd) is one of the most harmful heavy metals and environmental pollutants widely spread in nature [1]
We utilized the immortalized RBE4 cells that express all the enzymes and transporters considered specific for the blood–brain barrier endothelium with similar characteristics to those expected from in vivo analyses [69,70,71,72,73]
Our data showed that Cd induced a rapid reactive oxygen species (ROS) increase, reachinTghuitss, tpoeadkelainte5atme itnhepousntd-terrelaytimngenmt ewchitahnCisdm, sthuagtgtersitgignegrsthCadt -tdheepienndduecntitoTnJ oafnadncoyxtoidskaetilveteal starletsesrarteisopnos,nwseeiesxaamveinryedeaRrOlySepvreondtuicntitohne. cOeullrudlaartaresahcotiwoend. tThhaet Cpdeaikndaut c5edmainrawpaids tRhOenS rinapcriedalsye, forleloawcheidngbyitsapdeeacklinate5omf RinOpSolesvt-etrlseathtmatetnetnwdeitdhtCo dd,issaupgpgeeasrtiantg1t0hmatitnhaefitnedr uthceticohnaollfeanngeoxwiditahtiCvde.sYtreets,s wreeospbosenrsveedistahavteRryOeSalrelvyeelsviennctreinastehdeacgealliunlaafrterrea2chti.oTnh. eTlhaettepreraeksualtts5amreininwaagsretehmenenrtawpiidthlypfroelvloiowuesd wboyrkaddeemcloinnestoraftRinOgSthleavt eclhsrtohnaitc teexnpdoesdurteo tdoisCadppinedarucaetd10himghinleavfetelsr othf eROchSalalnendgceonwtirtihbuCtded

Summary

Introduction

Cadmium (Cd) is one of the most harmful heavy metals and environmental pollutants widely spread in nature [1]. Cd toxicity is well known to affect a number of organ and tissues both at acute and chronic doses. The effect of Cd exposure is strictly dose-dependent: at high doses, Cd can progressively elicit cell injury, cell death, and organ failure, and at low doses it may modulate specific mechanisms without marked cellular toxicity [8]. Many in vivo and in vitro studies provide evidence that Cd induces neurotoxicity and damage to the peripheral nervous system (PNS) and central nervous system (CNS) [8,9,10,11,12,13] with a wide spectrum of clinical symptoms They include neurological disturbances [14], neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [15], amyotrophic lateral sclerosis, multiple sclerosis [16,17], myalgic encephalomyelitis [18], olfactory dysfunction [19], peripheral neuropathy [20,21], mental retardation, and learning disabilities

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