Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity.
Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity.
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DOI：
10.1016/j.kint.2019.11.012
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发表时间：
2020-04
影响因子：
19.6
通讯作者：
Shu Y
中科院分区：
文献类型：
--
作者：
Yang H;Tang J;Guo D;Zhao Q;Wen J;Zhang Y;Obianom ON;Zhou S;Zhang W;Shu Y
农田污染和吸烟盛行导致的镉在肾脏积累和暴露仍然是一个不可忽视的人类健康问题。尽管镉暴露与多种肾脏疾病的发病率增加有关，但人们对其对肾脏药物处置和患者反应的影响知之甚少。在这里，我们报告镉暴露显着增加了有机阳离子转运蛋白 2 (OCT2) 的活性，有机阳离子转运蛋白 2 (OCT2) 是美国联邦药物管理局药物开发评估指南中推荐的一种关键的肾脏药物转运蛋白。镉在体外和体内均增强了 OCT2 向细胞膜的运输。在体外细胞研究中，发现镉介导的 OCT2 易位机制涉及丝氨酸/苏氨酸蛋白激酶 AKT2、钙/钙调蛋白和 AKT 底物 AS160 之间的蛋白质-蛋白质相互作用。形成的蛋白质复合物可以选择性地促进 AKT2 在 T309 处的磷酸化，从而诱导 OCT2 易位到质膜。此外，镉暴露通过增加顺铂（一种 OCT2 底物）在小鼠肾脏中的积累，显着加剧了顺铂诱导的肾毒性。一致地，接受顺铂化疗的宫颈癌患者的血浆镉水平与肾功能改变之间存在显着相关性。因此，我们的研究表明，镉暴露引起的膜转运蛋白分布是肾脏药物处置和反应广泛变化的一个先前未被认识的因素。
Renal accumulation and exposure of cadmium originating from pollution in agricultural land and the prevalence of cigarette smoking remains an unneglectable human health concern. Whereas cadmium exposure has been correlated with increased incidence of a variety of kidney diseases, little is known pertaining to its effect on renal drug disposition and response in patients. Here, we report that cadmium exposure significantly increased the activity of organic cation transporter 2 (OCT2), a critical renal drug transporter recommended in United States Federal Drug Administration guidance for assessment during drug development. Cadmium enhanced OCT2 trafficking to the cell membrane both in vitro and in vivo. Mechanistically cadmium-mediated OCT2 translocation was found to involve protein-protein interaction between serine/threonine-protein kinase AKT2, calcium/calmodulin and the AKT substrate AS160 in in vitro cellular studies. The formed protein complex could selectively facilitate phosphorylation of AKT2 at T309, which induced translocation of OCT2 to the plasma membrane. Moreover, cadmium exposure markedly exacerbated nephrotoxicity induced by cisplatin, an OCT2 substrate, by increasing its accumulation in the mouse kidney. Consistently, there was a significant correlation between plasma cadmium level and alteration of renal function in cervical cancer patients who underwent chemotherapy with cisplatin. Thus, our studies suggest that membrane transporter distribution induced by cadmium exposure is a previously unrecognized factor for the broad variation in renal drug disposition and response.
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影响因子：
6.7
作者：
通讯作者：
--
影响因子：
4.8
作者：
Kane, S;Sano, H;Lienhard, GE
通讯作者：
Lienhard, GE
DOI：
10.1080/009841099158123
发表时间：
1999-02-12
期刊：
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A
影响因子：
--
作者：
Benedetti, JL;Samuel, O;Gingras, S
通讯作者：
Gingras, S
影响因子：
7.7
作者：
Kramer, Henning F.;Taylor, Eric B.;Goodyear, Laurie J.
通讯作者：
Goodyear, Laurie J.
影响因子：
3.8
作者：
Coticchia, Christine M.;Revankar, Chetana M.;Johnson, Michael D.
通讯作者：
Johnson, Michael D.