Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity

American Journal of Physiology. Renal Physiology
Liping SunZheng Dong

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 ...Continue Reading

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Citations

Nov 30, 2019·Frontiers in Pharmacology·Jose Luis Morgado-PascualMarta Ruiz-Ortega
Mar 10, 2020·American Journal of Physiology. Renal Physiology·Zhixia SongZheng Dong
Mar 7, 2021·International Journal of Molecular Sciences·Anne GrunenwaldMarie Frimat
Jun 3, 2021·Pharmaceuticals·Pía LorenLuis A Salazar
Feb 24, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Chao-Yue SunBing Feng
Apr 23, 2021·Canadian Journal of Physiology and Pharmacology·Salwa Abdel-Tawab IbrahimHanaa Mohamed Khalaf

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Methods Mentioned

BETA
histone acetylation
fluorescence microscopy
acetylation

Software Mentioned

GraphPad Prism
GraphPad
ImageJ

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