Dong Yingying, Wu Luyao, Xu Xiaoying, Shen Siqi, Yang Haowen, Shao Yanfei
Hangzhou Hospital of Traditional Chinese Medicine (Affiliated Hangzhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University), Hangzhou, Zhejiang, China; Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Drug Metab Dispos. 2025 Jul;53(7):100097. doi: 10.1016/j.dmd.2025.100097. Epub 2025 May 13.
Acute kidney injury (AKI) is a worldwide health issue with risk of progressing to chronic kidney disease (CKD). The kidney harbors various transporters that may be involved in certain disease processes, in addition to mediating drug transport. Kidney injury may compromise the effectiveness and safety of medications by disturbing functions of these transporters. However, so far, there is a poor understanding of the changes in transporters and their mechanisms during AKI-to-CKD transition. In the present study, the expression of organic anion transporter 2 (OAT2) was found to be gradually decreased through bioinformatics analysis during AKI-to-CKD transition. Subsequent experiments via quantitative reverse-transcription polymerase chain reaction and western blot validated gradual reduction of OAT2 mRNA and protein levels during AKI-to-CKD transition. Pharmacokinetic studies revealed that OAT2 downregulation during AKI-to-CKD transition led to increased plasma exposure of its substrate, acyclovir. Metabolomics identified a gradual increase in taurodeoxycholic acid (TDCA) levels during AKI-to-CKD transition. Further in vitro experiments demonstrated that TDCA activated the farnesoid X receptor (FXR) in a concentration-dependent manner, leading to suppressed OAT2 expression. Both in vivo and in vitro experiments indicated that downregulated OAT2 expression induced by TDCA could be reversed by FXR inhibitor (guggulsterone) or by knocking down FXR. In conclusion, a gradual increase in TDCA levels plays a pivotal role in mediating FXR activation, which consequently disrupts the expression and function of renal OAT2 during AKI-to-CKD transition, resulting in increased drug plasma exposure. These findings emphasize the importance of precision medicine for AKI-to-CKD patients using OAT2 substrate drugs, providing a robust theoretical foundation for rational medications and treatment strategies tailored to special populations. SIGNIFICANCE STATEMENT: This study for the first time identified a gradual decrease in organic anion transporter 2 expression during acute kidney injury-to- chronic kidney disease transition, leading to increased plasma exposure of acyclovir. There existed increased taurodeoxycholic acid levels during acute kidney injury to chronic kidney disease transition, which could inhibit organic anion transporter 2 expression by activating the farnesoid X receptor.
急性肾损伤（AKI）是一个全球性的健康问题，存在进展为慢性肾脏病（CKD）的风险。肾脏含有多种转运蛋白，这些转运蛋白除了介导药物转运外，还可能参与某些疾病过程。肾损伤可能通过干扰这些转运蛋白的功能而损害药物的有效性和安全性。然而，到目前为止，人们对AKI向CKD转变过程中转运蛋白的变化及其机制了解甚少。在本研究中，通过生物信息学分析发现，在AKI向CKD转变过程中，有机阴离子转运蛋白2（OAT2）的表达逐渐降低。随后通过定量逆转录聚合酶链反应和蛋白质印迹法进行的实验证实了在AKI向CKD转变过程中OAT2 mRNA和蛋白质水平逐渐降低。药代动力学研究表明，在AKI向CKD转变过程中OAT2下调导致其底物阿昔洛韦的血浆暴露增加。代谢组学分析确定在AKI向CKD转变过程中牛磺脱氧胆酸（TDCA）水平逐渐升高。进一步的体外实验表明，TDCA以浓度依赖的方式激活法尼酯X受体（FXR），导致OAT2表达受到抑制。体内和体外实验均表明，FXR抑制剂（古古甾酮）或敲低FXR可逆转TDCA诱导的OAT2表达下调。总之，TDCA水平的逐渐升高在介导FXR激活中起关键作用，这进而在AKI向CKD转变过程中破坏肾OAT2的表达和功能，导致药物血浆暴露增加。这些发现强调了对使用OAT2底物药物的AKI向CKD患者进行精准医学治疗的重要性，为针对特殊人群的合理用药和治疗策略提供了坚实的理论基础。意义声明：本研究首次发现急性肾损伤向慢性肾损伤转变过程中有机阴离子转运蛋白2表达逐渐降低，导致阿昔洛韦血浆暴露增加。急性肾损伤向慢性肾损伤转变过程中牛磺脱氧胆酸水平升高，可通过激活法尼酯X受体抑制有机阴离子转运蛋白2表达。
