Key Renal Laboratory of Shenzhen, Department of Nephrology, The Second Clinical Medical College of Jinan University , Shenzhen , China.
Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center , Augusta, Georgia.
Am J Physiol Renal Physiol. 2018 Sep 1;315(3):F469-F478. doi: 10.1152/ajprenal.00527.2017. Epub 2018 May 16.
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.
顺铂作为一种有效的化疗药物，也因其副作用而臭名昭著，包括肾脏的肾毒性，因此迫切需要确定肾保护剂。顺铂肾毒性涉及表观遗传调控，包括组蛋白乙酰化的变化。溴结构域和末端（BET）蛋白是组蛋白乙酰化表观遗传密码的“读取器”。在这里，我们研究了 BET 蛋白小分子抑制剂 JQ1 对肾脏的潜在保护作用。我们发现 JQ1 显著改善了顺铂诱导的小鼠肾毒性，这可通过肾功能、组织病理学和肾小管细胞凋亡的测量来衡量。JQ1 还部分预防了顺铂治疗期间小鼠的体重减轻。一致地，JQ1 抑制了顺铂诱导的肾近端小管细胞凋亡。从机制上讲，JQ1 抑制了顺铂诱导的 p53 和 Chk2 的磷酸化或激活，这是 DNA 损伤反应中的关键事件。JQ1 还减弱了顺铂诱导的 MAP 激酶（p38、ERK1/2 和 JNK）的激活。此外，JQ1 增强了抗氧化基因的表达，包括核因子红细胞 2 相关因子 2 和血红素加氧酶-1，同时减少了诱导型一氧化氮合酶的硝化蛋白的表达。JQ1 并未抑制 A549 非小细胞肺癌细胞和 AGS 胃癌细胞中顺铂诱导的细胞凋亡。这些结果表明，JQ1 可能通过抑制 DNA 损伤反应、p53、MAP 激酶和氧化/硝化应激途径来保护顺铂肾毒性。
