Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity
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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Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting
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