Abstract: SA-PO101
Molecular Pathways Driving Omeprazole Nephrotoxicity
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Fontecha, Miguel, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain
- Martin-Sanchez, Diego, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain
- Martínez Moreno, Julio Manuel, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain
- Ortiz, Alberto, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain
- Sanz, Ana Belen, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain
Background
Omeprazole, a proton pump inhibitor used to treat peptic ulcer and gastroesophageal reflux disease, has been associated to chronic kidney disease and acute interstitial nephritis. However, whether omeprazole is toxic to renal cells is unknown. Omeprazole has a lethal effect over some cancer cells, and cell death is a key process in kidney disease.
Methods
Thus, we evaluated the potential lethal effect of omeprazole over cultured tubular proximal cells.
Results
Omeprazole induces dose-dependent cell death in human and murine proximal tubular cell lines and in human primary proximal tubular cell cultures. Increased cell death was observed at the high doses used in cancer cell studies and also at lower concentrations similar to those in peptic ulcer patient serum. Cell death induced by omeprazole has features of necrosis such as annexinV/7-AAD staining and irregular chromatin condensation. Weak activation of caspase-3 was observed but inhibitors of caspases (carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone,zVAD), necroptosis (necrostatin-1) or ferroptosis (ferrostatin-1) did not prevent omeprazole-induced death.
However, omeprazole induced a dose-dependent and early increase in ROS production as assessed by CM-H2DCFDA staining and flow cytometry. ROS production increased in mitochondria, as assessed by MitoSOX staining, and by NADPH activity role, determined by lucigenin assay. Moreover, the antioxidant molecule N-Acetylcysteine (NAC) partially prevented omeprazole-induced ROS production and cell death as assessed by the MTT assay and by annexin-V/7AAD staining. Omeprazole also induced lysosomal stress, evidenced by an increase in lysosomal pH and this was also prevented by NAC.
Autophagy activation was also observed but blockade of autophagosome formation by 3-methyladenine did not decrease omeprazole-induced death. An adaptive increase in the expression of the antiapoptotic protein BclxL failed to protect the cells.
In mice, parenteral omeprazole increased tubular cell death and the expression of NGAL, a marker of renal injury.
Conclusion
In conclusion, omeprazole nephrotoxicity may be related to induction of oxidative stress and renal tubular cell death, supporting the biological plausibility for the epidemiological association of chronic proton pump inhibitor use to kidney disease.