1. Blockade of aryl hydrocarbon receptor restricts omeprazole-induced chronic kidney disease.
- Author
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Sun N, Zhang Y, Ding L, An X, Bai F, Yang Y, Yu K, Fan J, Liu L, Yang H, and Yang X
- Subjects
- Animals, Humans, Male, Mice, Basic Helix-Loop-Helix Transcription Factors metabolism, Basic Helix-Loop-Helix Transcription Factors genetics, Cell Line, Disease Models, Animal, Epithelial Cells metabolism, Epithelial Cells drug effects, Kidney Tubules pathology, Kidney Tubules metabolism, Kidney Tubules drug effects, RNA, Small Interfering metabolism, RNA, Small Interfering genetics, Cytochrome P-450 CYP1A1 metabolism, Cytochrome P-450 CYP1A1 genetics, Mice, Inbred C57BL, Mice, Knockout, Omeprazole pharmacology, Receptors, Aryl Hydrocarbon metabolism, Receptors, Aryl Hydrocarbon genetics, Renal Insufficiency, Chronic metabolism, Renal Insufficiency, Chronic drug therapy, Renal Insufficiency, Chronic etiology, Renal Insufficiency, Chronic chemically induced
- Abstract
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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2024
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