Cadmium exposure induces autophagy via PLC‐IP3‐IP3R signaling pathway in duck renal tubular epithelial cells
Cadmium exposure induces autophagy via PLC‐IP3‐IP3R signaling pathway in duck renal tubular epithelial cells
复制标题
DOI：
10.1002/tox.23626
复制
发表时间：
2022-08
影响因子：
4.5
通讯作者：
Huiling Guo;Bingyan Huang;Ting Cui;Xuesheng Chu;Wenjing Pu;Gang Huang;Chenghong Xing;Caiying Zhang
中科院分区：
文献类型：
--
作者：
Huiling Guo;Bingyan Huang;Ting Cui;Xuesheng Chu;Wenjing Pu;Gang Huang;Chenghong Xing;Caiying Zhang
镉(Cd)对动物是有害的，但Cd对鸭的肾毒性作用尚未完全阐明。为探讨镉通过PLC-IP3-IP3R途径对鸭肾小管上皮细胞钙稳态和自噬的影响，将原代鸭肾小管上皮细胞暴露于2.5μM和5.0μM CD以及5.0μM CD和10.0μM2-APB或0.125μM U-73122联合作用12 h(U-73122预处理1 h)。这些结果表明，Cd诱导的细胞内钙超载主要来自于细胞内的钙储存。Cd可引起细胞内[Ca~(2+)]MIT和[Ca~(2+)]c超载，[Ca~(2+)]ER降低，钙稳态相关因子(GRP78、GRP94、CRT、CaN、CaMKII、CaMKKβ)表达增加，磷脂酶C和IP3活性及IP3R表达增加，但2-APB逆转了细胞内钙的再分配。PLC抑制剂U-73122能显著缓解Cd对上述指标的影响。U-73122还能明显减少镉诱导的自噬小体数目和LC_3聚集点的数目，降低ATG5、LC_3A、LC_3B的基因表达水平和LC_3Ⅱ/LC_3I、BECLIN-1的蛋白水平，显著提高p62的基因和蛋白水平。综上所述，Cd诱导鸭肾小管上皮细胞[Ca~(2+)]_c超载主要来源于PLC-IP3-IP3R途径介导的ER~(2+)释放，进而触发鸭肾小管上皮细胞自噬。
Cadmium (Cd) is detrimental to animals, but nephrotoxic effects of Cd on duck have not been fully elucidated. To evaluate the impacts of Cd on Ca homeostasis and autophagy via PLC‐IP3‐IP3R pathway, primary duck renal tubular epithelial cells were exposed to 2.5 μM and 5.0 μM Cd, and combination of 5.0 μM Cd and 10.0 μM 2‐APB or 0.125 μM U‐73122 for 12 h (U‐73122 pretreated for 1 h). These results evidenced that Cd induced [Ca2+]c overload mainly came from intracellular Ca store. Cd caused [Ca2+]mit and [Ca2+]c overload with [Ca2+]ER decrease, elevated Ca homeostasis related factors (GRP78, GRP94, CRT, CaN, CaMKII, and CaMKKβ) expression, PLC and IP3 activities and IP3R expression, but subcellular Ca2+ redistribution was reversed by 2‐APB. PLC inhibitor U‐73122 dramatically relieved the changes of the above indicators induced by Cd. Additionally, U‐73122 obviously reduced the number of autophagosomes and LC3 accumulation spots, Atg5, LC3A, LC3B mRNA levels and LC3II/LC3I, Beclin‐1 protein levels induced by Cd, and markedly elevated p62 mRNA and protein levels. Overall, the results verified that Cd induced [Ca2+]c overload mainly originated from ER Ca2+ release mediated by PLC‐IP3‐IP3R pathway, then triggered autophagy in duck renal tubular epithelial cells.