Abstract
Cadmium (Cd), as an extremely toxic metal could accumulate in kidney and induce renal injury. Previous studies have proved that Cd impact on renal cell proliferation, autophagy and apoptosis, but the detoxification drugs and the functional mechanism are still in study. In this study, we used mouse renal tubular epithelial cells (mRTECs) to clarify Cd-induced toxicity and signaling pathways. Moreover, we proposed to elucidate the prevent effect of activation of Ca2+ sensing receptor (CaSR) by Calcimimetic (R-467) on Cd-induced cytotoxicity and underlying mechanisms. Cd induced intracellular Ca2+ elevation through phospholipase C-inositol 1, 4, 5-trisphosphate (PLC) followed stimulating p38 mitogen-activated protein kinases (MAPK) activation and suppressing extracellular signal-regulated kinase (ERK) activation, which leaded to increase apoptotic cell death and inhibit cell proliferation. Cd induced p38 activation also contribute to autophagic flux inhibition that aggravated Cd induced apoptosis. R-467 reinstated Cd-induced elevation of intracellular Ca2+ and apoptosis, and it also increased cell proliferation and restored autophagic flux by switching p38 to ERK pathway. The identification of the activation of CaSR-mediated protective pathway in renal cells sheds light on a possible cellular protective mechanism against Cd-induced kidney injury.
Highlights
Occupational and environmental pollutant of Cadmium (Cd) caused various organs damage, especially the kidney, which is the major site of Cd accumulation[1,2,3]
Previous studies suggested that Cd disrupted intracellular Ca2+ homeostasis through reducing the influx of extracellular Ca2+23,24, or increasing Ca2+ release from intracellular Ca2+ store[22,25] and resulting in cell apoptosis of renal tubular cells[21,22]
cation-sensing receptor (CSR) was different from calcium-sensing receptor (CaSR) and CaSR agonist neomycin could diminish the effect of Cd on intracellular Ca2+27
Summary
Occupational and environmental pollutant of Cadmium (Cd) caused various organs damage, especially the kidney, which is the major site of Cd accumulation[1,2,3]. Intracellular Ca2+ signaling pathway mediated Cd-induced autophagy[17], which played a renoprotective role in www.nature.com/scientificreports/ Both acute kidney injury and chronic kidney diseases[31], and was indicated as a protective way against Cd-induced apoptosis in lung epithelial fibroblast cells WI3832, pheochromocytoma cell line PC-1233, and rat renal tubular cells[34]. A great number of studies have show that Cd regulates the functions of many Ca2+-dependent regulatory proteins such as protein kinase C (PKC), mitogen-activated protein kinase (MAPK), calmodulin (CaM), and calcium/calmodulin-dependent protein kinase II (CaMKII), inducing dysregulation of intracellular Ca2+ homeostasis[16,35,36,37,38,39,40,41] These intracellular signals can be induced by the extracellular calcium-sensing receptor (CaSR), a G-protein-coupled receptor (GPCR), which is responsible for the control of calcium homeostasis in body fluids[42,43,44,45,46]. It is still unknown whether there is competition or crosstalk between CaSR and CSR mediated pathways
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