title: Salidroside ameliorates Cd-induced calcium overload and gap junction dysfunction in BRL 3A rat liver cells.
abstract: It is known that cadmium (Cd) induces cytotoxicity via Ca(2+) signaling, although the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced cytotoxicity in BRL 3A cells, a rat liver cell line. We observed that Cd treatment was associated with a time-dependent decrease in cell index (CI) in BRL 3A cells. Mechanistically, we observed that Cd exposure was associated with decreased expression of Cx43, P-Cx43, and Cx32. Specifically, Cx43 was decreased at the site of cell-cell junctions at the cell membrane, corresponding to a decrease in gap junctional intercellular connections (GJICs). We also found that Cd triggered a rise in the intracellular free Ca(2+) concentration ([Ca(2+)]i), and the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis, acetoxymethyl ester (BAPTA-AM), prevented the Cd-induced decrease in CI. On the other hand, the gap junction blocker 18-β-glycyrrhetinic acid (GA) and the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin exacerbated cytotoxic injury induced by Cd via further elevating [Ca(2+)]i, The extracellular calcium chelator ethylene glycol tetraacetic acid could partly attenuate Cd-induced calcium elevation but had little effect on GA combined Cd. Furthermore, salidroside as a protective agent prevented Cd-induced GJIC inhibition and calcium overload. Our findings suggest that Cd triggers elevation of [Ca(2+)]i via mainly stimulating Ca(2+) release from intracellular Ca(2+) storage organelles and inhibiting GJIC, causing cytotoxic injury, and salidroside could be used to prevent Cd-induced cytotoxicity.
authors.affiliation: College of Veterinary Medicine, Yangzhou University, 88 South University Ave., Yangzhou, Jiangsu, 225009, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zou
authors.forename: Di
authors.initials: D
authors.lastname: Hu
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhao
authors.forename: Junze
authors.initials: J
authors.lastname: Xie
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianhong
authors.initials: J
authors.lastname: Gu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Jianchun
authors.initials: J
authors.lastname: Bian
authors.forename: Zongping
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002104:Cadmium / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism*; D005960:Glucosides / Q000494:pharmacology*; D018613:Microscopy, Confocal; D010636:Phenols / Q000494:pharmacology*; D051381:Rats
chemical_list: D005960:Glucosides; D010636:Phenols; D002104:Cadmium; C009172:rhodioloside; D002118:Calcium