1. Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity.
- Author
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Sun L, Liu J, Yuan Y, Zhang X, and Dong Z
- Subjects
- A549 Cells, Animals, Checkpoint Kinase 2 metabolism, Cytoprotection, DNA Damage drug effects, Disease Models, Animal, Enzyme Activation, Humans, Kidney Diseases chemically induced, Kidney Diseases metabolism, Kidney Diseases pathology, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal pathology, Kidney Tubules, Proximal physiopathology, Male, Mice, Inbred C57BL, Mitogen-Activated Protein Kinases metabolism, Nitrosative Stress drug effects, Phosphorylation, Signal Transduction drug effects, Tumor Suppressor Protein p53 metabolism, Weight Loss drug effects, Antioxidants pharmacology, Apoptosis drug effects, Azepines pharmacology, Cisplatin, Kidney Diseases prevention & control, Kidney Tubules, Proximal drug effects, Oxidative Stress drug effects, Triazoles pharmacology
- Abstract
As a potent chemotherapy drug, cisplatin is also notorious for its side-effects including nephrotoxicity in kidneys, presenting a pressing need to identify renoprotective agents. Cisplatin nephrotoxicity involves epigenetic regulations, including changes in histone acetylation. Bromodomain and extraterminal (BET) proteins are "readers" of the epigenetic code of histone acetylation. Here, we investigated the potential renoprotective effects of JQ1, a small molecule inhibitor of BET proteins. We show that JQ1 significantly ameliorated cisplatin-induced nephrotoxicity in mice as indicated by the measurements of kidney function, histopathology, and renal tubular apoptosis. JQ1 also partially prevented the body weight loss during cisplatin treatment in mice. Consistently, JQ1 inhibited cisplatin-induced apoptosis in renal proximal tubular cells. Mechanistically, JQ1 suppressed cisplatin-induced phosphorylation or activation of p53 and Chk2, key events in DNA damage response. JQ1 also attenuated cisplatin-induced MAP kinase (p38, ERK1/2, and JNK) activation. In addition, JQ1 enhanced the expression of antioxidant genes including nuclear factor erythroid 2-related factor 2 and heme oxygenase-1, while diminishing the expression of the nitrosative protein inducible nitric oxide synthase. JQ1 did not suppress cisplatin-induced apoptosis in A549 nonsmall cell lung cancer cells and AGS gastric cancer cells. These results suggest that JQ1 may protect against cisplatin nephrotoxicity by suppressing DNA damage response, p53, MAP kinases, and oxidative/nitrosative stress pathways.
- Published
- 2018
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