Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells.
Detrimental effects of Notch1 signaling activated by cadmium in renal proximal tubular epithelial cells.
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DOI：
10.1038/cddis.2014.339
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发表时间：
2014-08-14
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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我们研究了Notch 1信号传导及其与其他信号传导途径（包括p53和磷脂酰肌醇-3-激酶（PI 3 K）/Akt）的串扰在镉诱导的HK-2人近端肾小管上皮细胞细胞损伤中的作用。暴露于氯化镉（CdCl 2）后，Notch细胞内结构域（NICD）（Notch 1受体的切割形式）的水平增加并在核部分中积累。用siRNA敲除Notch 1或用γ-分泌酶抑制剂DAPT（N-[N-（3，5-difluorophenacetyl-L-alanyl）]-S-phenylglycine t-butyl ester）处理可防止CdCl 2诱导的HK-2细胞形态学改变和细胞活力降低。敲除Notch 1受体的配体Jagged 1或Jagged 2可部分抑制镉的细胞毒性。用pifithrin-α抑制p53活性或用LY 294002抑制PI 3 K抑制CdCl 2诱导的细胞损伤和Notch 1-NICD升高。此外，治疗与表皮生长因子受体（EGFR）抑制剂，AG 1478，和胰岛素样生长因子-1受体抑制剂，PPP，抑制Notch 1-NICD积累和Akt磷酸化的HK-2细胞暴露于氯化镉。然而，敲除Notch 1并不影响氯化镉诱导的p53积累和磷酸化，但抑制EGFR，Akt和p70 S6激酶的磷酸化。Notch 1的缺失抑制CdCl 2诱导的E-cadherin表达的减少和Snail表达的升高。此外，用SB 216763（糖原合成酶激酶-3的抑制剂）处理抑制了LY 294002处理降低暴露于CdCl 2的HK-2细胞中Snail表达的效力。Snail的siRNA敲除可部分抑制CdCl 2诱导的HK-2细胞E-cadherin表达减少和细胞损伤。这些结果表明，镉暴露诱导的Notch 1信号在肾近端小管细胞与p53和PI 3 K/Akt信号通路的协同激活激活的激活;由此产生的表达的蜗牛，E-钙粘蛋白表达的阻遏物，可能会导致细胞损伤，通过减少细胞-细胞粘附。
We examined the roles of Notch1 signaling and its cross-talk with other signaling pathways, including p53 and phosphatidylinositol-3-kinase (PI3K)/Akt, in cadmium-induced cellular damage in HK-2 human renal proximal tubular epithelial cells. Following exposure to cadmium chloride (CdCl2), the level of Notch intracellular domain (NICD), the cleaved form of the Notch1 receptor, was increased and accumulated in the nuclear fraction. Knockdown of Notch1 with siRNA or treatment with the γ-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester), prevented CdCl2-induced morphological change of HK-2 cells and reduction of cell viability. Knockdown of Jagged1 or Jagged2, the ligands of the Notch1 receptor, partially suppressed cadmium cytotoxicity. Inhibition of p53 activity with pifithrin-α or inhibition of PI3K with LY294002 suppressed CdCl2-induced cellular damage and elevation of Notch1-NICD. In addition, treatment with the epidermal growth factor receptor (EGFR) inhibitor, AG1478, and the insulin-like growth factor-1 receptor inhibitor, PPP, suppressed both Notch1-NICD accumulation and Akt phosphorylation in HK-2 cells exposed to CdCl2. However, knockdown of Notch1 did not affect CdCl2-induced p53 accumulation and phosphorylation but suppressed phosphorylation of EGFR, Akt, and p70 S6 kinase. Depletion of Notch1 suppressed CdCl2-induced reduction of E-cadherin expression and elevation of Snail expression. Furthermore, treatment with SB216763, an inhibitor of glycogen synthase kinase-3, suppressed the potency of LY294002 treatment to reduce Snail expression in HK-2 cells exposed to CdCl2. Knockdown of Snail with siRNA partially prevented HK-2 cells from CdCl2-induced reduction of E-cadherin expression and cellular damage. These results suggest that cadmium exposure induces the activation of Notch1 signaling in renal proximal tubular cells with cooperative activation by the p53 and PI3K/Akt signaling pathways; the resultant expression of Snail, a repressor of E-cadherin expression, might lead to cellular damage by decreasing cell–cell adhesion.
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影响因子：
37.3
作者：
Chakraborty PK;Lee WK;Molitor M;Wolff NA;Thévenod F
通讯作者：
Thévenod F
影响因子：
4
作者：
Basile, Antonio;Biziato, Daniela;Cajone, Francesco
通讯作者：
Cajone, Francesco
DOI：
10.1007/978-1-4614-0899-4_15
发表时间：
2012-01-01
期刊：
NOTCH SIGNALING IN EMBRYOLOGY AND CANCER
影响因子：
--
作者：
Dang, Thao P.
通讯作者：
Dang, Thao P.
影响因子：
7.4
作者：
Chen, Long;Xu, Baoshan;Liu, Lei;Luo, Van;Zhou, Hongyu;Chen, Wenxing;Shen, Tao;Han, Xiuzhen;Kontos, Christopher D.;Huang, Shile
通讯作者：
Huang, Shile
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG