Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
J Mol Med (Berl). 2024 May;102(5):679-692. doi: 10.1007/s00109-024-02429-5. Epub 2024 Mar 8.
Chronic kidney disease (CKD) is the 16th leading cause of mortality worldwide. Clinical studies have raised that long-term use of omeprazole (OME) is associated with the morbidity of CKD. OME is commonly used in clinical practice to treat peptic ulcers and gastroesophageal reflux disease. However, the mechanism underlying renal failure following OME treatment remains mostly unknown and the rodent model of OME-induced CKD is yet to be established. We described the process of renal injury after exposure to OME in mice; the early renal injury markers were increased in renal tubular epithelial cells (RTECs). And after long-term OME treatment, the OME-induced CKD mice model was established. Herein, aryl hydrocarbon receptor (AHR) translocation appeared after exposure to OME in HK-2 cells. Then for both in vivo and in vitro, we found that Ahr-knockout (KO) and AHR small interfering RNA (siRNA) substantially alleviated the OME-induced renal function impairment and tubular cell damage. Furthermore, our data demonstrate that antagonists of AHR and CYP1A1 could attenuate OME-induced tubular cell impairment in HK-2 cells. Taken together, these data indicate that OME induces CKD through the activation of the AHR-CYP axis in RTECs. Our findings suggest that blocking the AHR-CYP1A1 pathway acts as a potential strategy for the treatment of CKD caused by OME. KEY MESSAGES: We provide an omeprazole-induced chronic kidney disease (CKD) mice model. AHR activation and translocation process was involved in renal tubular damage and promoted the occurrence of CKD. The process of omeprazole nephrotoxicity can be ameliorated by blockade of the AHR-CYP1A1 axis.
慢性肾脏病（CKD）是全球第 16 大死亡原因。临床研究表明，长期使用奥美拉唑（OME）与 CKD 的发病率有关。OME 常用于临床治疗消化性溃疡和胃食管反流病。然而，OME 治疗后导致肾功能衰竭的机制在很大程度上尚不清楚，也尚未建立 OME 诱导的 CKD 啮齿动物模型。我们描述了 OME 暴露后小鼠肾脏损伤的过程；早期肾损伤标志物在肾小管上皮细胞（RTEC）中增加。并且在长期 OME 治疗后，建立了 OME 诱导的 CKD 小鼠模型。在此，我们发现 AHR 在 HK-2 细胞中 OME 暴露后发生易位。然后，无论是在体内还是体外，我们都发现 Ahr 基因敲除（KO）和 AHR 小干扰 RNA（siRNA）可显著减轻 OME 诱导的肾功能损害和肾小管细胞损伤。此外，我们的数据表明 AHR 和 CYP1A1 的拮抗剂可减轻 HK-2 细胞中 OME 诱导的肾小管细胞损伤。综上所述，这些数据表明 OME 通过激活 RTEC 中的 AHR-CYP 轴诱导 CKD。我们的研究结果表明，阻断 AHR-CYP1A1 途径可能是治疗 OME 引起的 CKD 的一种潜在策略。
