Salidroside ameliorates Cd-induced calcium overload and gap junction dysfunction in BRL 3A rat liver cells

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.