Role of PLC/IP3/IP3R axis in excess molybdenum exposure induced apoptosis in duck renal tubular epithelial cells
Role of PLC/IP3/IP3R axis in excess molybdenum exposure induced apoptosis in duck renal tubular epithelial cells
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DOI：
10.1002/tox.23956
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发表时间：
2023-09-07
影响因子：
4.5
通讯作者：
Dai，Xueyan
中科院分区：
文献类型：
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作者：
Guo，Huiling;Zhang，Caiying;Dai，Xueyan
过量钼对动物有害，但其肾毒性尚未得到全面解释。为探讨过量钼对原代培养的鸭肾小管上皮细胞钙稳态和凋亡的影响，分别用480 μM和960 μM钼，以及960 μM钼与10 μM 2-APB或0.125 μM U-73122联合作用12 h（U-73122预处理1 h）。结果表明，Mo引起的[Ca ~（2+）] c增加主要来源于细胞内Ca ~（2+）的贮存。钼暴露降低[Ca 2 +]ER，升高[Ca 2 +]mit，[Ca 2 +]c和Ca稳态相关因子（钙蛋白酶，CaN，CRT，GRP 94，GRP 78和CaMK II）的表达。2-APB可通过抑制IP 3R有效逆转亚细胞内Ca 2+再分布，证实Mo诱导的[Ca 2 +]覆盖负荷来源于内质网。此外，PLC抑制剂U-73122可显著减轻上述变化，并显著降低凋亡细胞数、巴克-1、Bax、cleaved-Caspase-3/Caspase-3的表达，并显著增加Bcl-xL、Bcl-2和Bcl-2/Bax比值的表达。以上结果证实，内质网通过PLC/IP 3/IP 3R轴释放Ca 2+是导致[Ca 2 +]覆盖的主要原因，进而刺激鸭肾小管上皮细胞凋亡。
Excess molybdenum (Mo) is harmful to animals, but its nephrotoxicity has not been comprehensively explained. To appraise the influences of excess Mo on Ca homeostasis and apoptosis via PLC/IP3/IP3R axis, primary duck renal tubular epithelial cells were exposed to 480 μM and 960 μM Mo, and joint of 960 μM Mo and 10 μM 2‐APB or 0.125 μM U‐73122 for 12 h (U‐73122 pretreated for 1 h), respectively. The data revealed that the increment of [Ca2+]cinduced by Mo mainly originated from intracellular Ca storage. Mo exposure reduced [Ca2+]ER, elevated [Ca2+]mit, [Ca2+]c, and the expression of Ca homeostasis‐related factors (Calpain, CaN, CRT, GRP94, GRP78 and CaMKII). 2‐APB could effectively reverse subcellular Ca2+redistribution by inhibiting IP3R, which confirmed that [Ca2+]coverload induced by Mo originated from ER. Additionally, PLC inhibitor U‐73122 remarkably mitigated the change, and dramatically reduced the number of apoptotic cells, the expression of Bak‐1, Bax, cleaved‐Caspase‐3/Caspase‐3, and notably increased the expression of Bcl‐xL, Bcl‐2, and Bcl‐2/Bax ratio. Overall, the results confirmed that the Ca2+liberation of ER via PLC/IP3/IP3R axis was the main cause of [Ca2+]coverload, and then stimulated apoptosis in duck renal tubular epithelial cells.