Kidney Cortical Transporter Expression across Species Using Quantitative Proteomics
Kidney Cortical Transporter Expression across Species Using Quantitative Proteomics
复制标题
DOI：
10.1124/dmd.119.086579
复制
发表时间：
2019-08-01
影响因子：
3.9
通讯作者：
Prasad, Bhagwat
中科院分区：
文献类型：
--
作者：
Basit, Abdul;Radi, Zaher;Prasad, Bhagwat
对肾脏转运蛋白物种差异的了解有限，是预测人类药物引起的急性肾损伤、药物相互作用和药代动力学的关键知识差距。在这里，我们报告了 5 个物种（人、猴、狗、大鼠和小鼠）肾皮质中 19 种转运蛋白的蛋白质丰度数据。总体而言，除多药耐药蛋白1（MDR1）、有机阳离子转运蛋白（OCT）3和OCTN1外，临床前物种中所有19种膜转运蛋白的丰度均高于人类。在非人类灵长类动物中，可获得绝对数据的 12 种转运蛋白的总丰度比人类高 2.1 倍（P = 0.025），但这些转运蛋白在两个物种中的分布百分比相同。多药耐药相关蛋白 (MRP) 4、OCTN2、有机阴离子转运蛋白 (OAT) 2、钠/钾转运 ATP 酶、MRP3、SGLT2、OAT1、MRP1、MDR1 和 OCT2 表达不同，跨物种变异性为 8.2-、7.4-、6.1-、5.9-、5.4-、5.2-、分别是 4.1 倍、3.3 倍和 2.8 倍。性别差异仅在啮齿类动物和狗中显着。在人和猴子的 OAT1 与 MRP2/MRP4 以及 OCT2 与 MATE1 中观察到高蛋白质-蛋白质相关性。跨物种和性别依赖性蛋白质丰度数据对于从动物到人类的药物清除率缩放以及肾脏生理学的机制理解和药物开发中新治疗候选物消除肾脏毒性的风险都很重要。
Limited understanding of species differences in kidney transporters is a critical knowledge gap for prediction of drug-induced acute kidney injury, drug interaction, and pharmacokinetics in humans. Here, we report protein abundance data of 19 transporters in the kidney cortex across five species (human, monkey, dog, rat, and mouse). In general, the abundance of all of the 19 membrane transporters was higher in preclinical species compared with human except for multidrug resistance protein 1 (MDR1), organic cation transporter (OCT) 3, and OCTN1. In nonhuman primate, the total abundance of 12 transporters for which absolute data were available was 2.1-fold higher (P = 0.025) relative to human but the percentage of distribution of these transporters was identical in both species. Multidrug resistance-associated protein (MRP) 4, OCTN2, organic anion transporter (OAT) 2, sodium/potassium-transporting ATPase, MRP3, SGLT2, OAT1, MRP1, MDR1, and OCT2 were expressed differently with cross-species variabilities of 8.2-, 7.4-, 6.1-, 5.9-, 5.4-, 5.2-, 4.1-, 3.3-, and 2.8-fold, respectively. Sex differences were only significant in rodents and dog. High protein-protein correlation was observed in OAT1 versus MRP2/MRP4 as well as OCT2 versus MATE1 in human and monkey. The cross-species and sex-dependent protein abundance data are important for animal to human scaling of drug clearance as well as for mechanistic understanding of kidney physiology and derisking of kidney toxicity for new therapeutic candidates in drug development.