Save Kidneys in Cisplatin Chemotherapy by blocking HDAC6

项目摘要 顺铂及其衍生物是目前应用最广泛的实体瘤化疗药物。 然而，顺铂在用于癌症治疗过程中会导致肾脏损伤。目前，没有治疗方法可用于 除支持性护理外，顺铂所致的急、慢性肾损伤。这个项目的目标是阐明 组蛋白脱乙酰基酶6在顺铂致肾损伤、纤维化及慢性肾损伤中的作用及机制 肾脏疾病(CKD)，并确定HDAC6抑制作为一种新的肾脏保护方法。我们的预赛 研究表明，HDAC6在单次大剂量顺铂诱导的急性肾损伤中表达上调。 在此模型中，小鼠和HDAC6的药理抑制可减轻肾小管细胞凋亡和AKI。HDAC6 反复小剂量顺铂治疗也是高度诱导的，伴随着肾间质 纤维化、表皮生长因子受体(EGFR)持续激活和自噬以及脱乙酰化 纤毛分解的关键过程--微管蛋白(α-tuBulin)。此外，顺铂治疗可导致原发灶缩短。 培养的肾上皮细胞纤毛，纤毛越短的细胞对顺铂诱导的作用越敏感 细胞凋亡。这些研究提供了HDAC6可能介导顺铂诱导的肾脏的初步证据 其潜在机制可能涉及表皮生长因子受体、自噬和纤毛解体。这些数据， 再加上已知的HDAC6在肿瘤中的促癌作用，导致了我们的假设，即阻断 HDAC6可能在顺铂化疗期间保护肾脏，同时增强其在肿瘤中的抗癌效果。 机制上，HDAC6可能通过激活EGFR参与顺铂诱导的肾脏问题。 肾小管细胞的自噬和初级纤毛的分解。为了检验这些假设，我们将 确定(1)在顺铂治疗期间，阻断HDAC6是否可以保护肾脏，同时增强肾脏的 化疗对肿瘤的影响；(2)HDAC6是否促进顺铂诱导的肾损伤、纤维化和 持续激活EGFR和自噬导致的CKD；以及(3)HDAC6是否介导纤毛解体 加重顺铂治疗后的肾脏损伤、纤维化和慢性肾脏病。这个多PI项目利用了 庄首钢博士在EGFR信号和表观遗传调控方面的互补专业知识和Dr。 郑东在自噬和顺铂肾毒性中的作用。成功完成拟议的研究将确定 HDAC6抑制对顺铂所致肾损伤和纤维化的治疗作用 潜在的机制，并确定在加强化疗的同时保护肾脏的新策略 功效。

Project Summary Cisplatin and its derivatives are the most widely used chemotherapeutic agents for treating solid tumors. However, cisplatin induces kidney injury during its use in cancer therapy. Currently, no treatment is available for cisplatin-induced acute and chronic kidney injury except supportive care. The goal of this project is to elucidate the role and mechanism of histone deacetylase 6 (HDAC6) in cisplatin-induced kidney injury, fibrosis and chronic kidney disease (CKD), and to identify HDAC6 inhibition as a novel approach for renoprotection. Our preliminary studies show that HDAC6 is up-regulated in acute kidney injury (AKI) induced by a single high-dose of cisplatin in mice and pharmacological inhibition of HDAC6 attenuates renal tubular apoptosis and AKI in this model. HDAC6 is also highly induced by repeated low-dose cisplatin treatment, which is accompanied by renal interstitial fibrosis, persistent activation of epidermal growth factor receptor (EGFR) and autophagy, and deacetylation of α-tubulin, a key process in cilium disassembly. Moreover, cisplatin treatment induces shortening of primary cilium in cultured renal epithelial cells, and the cells with shorter cilia are more sensitive to cisplatin-induced apoptosis. These studies provide preliminary evidence that HDAC6 may mediate cisplatin-induced kidney damage and that the underlying mechanism may involve EGFR, autophagy and ciliary disassembly. These data, together with a known cancer-promoting role of HDAC6 in tumors, have led to our hypothesis that blockade of HDAC6 may protect kidneys during cisplatin chemotherapy while enhancing its anti-cancer efficacy in tumors. Mechanistically, HDAC6 may contribute to cisplatin-induced kidney problems through the activation of EGFR and autophagy, and disassembly of primary cilium in renal tubular cells. To test these hypotheses, we will determine (1) whether blockade of HDAC6 can protect kidneys during cisplatin treatment while enhancing the chemotherapy effects in tumors; (2) whether HDAC6 contributes to cisplatin-induced renal injury, fibrosis and CKD by persistent activation of EGFR and autophagy; and (3) whether HDAC6-mediated ciliary disassembly aggravates kidney injury, fibrosis and CKD following cisplatin treatment. This multiple PI project takes advantage of the complementary expertise of Dr. Shougang Zhuang in EGFR signaling and epigenetic regulation and Dr. Zheng Dong in autophagy and cisplatin nephrotoxicity. Successful completion of the proposed studies will define the therapeutic effect of HDAC6 inhibition on cisplatin-induced renal damage and fibrosis, elucidate the underlying mechanisms, and identify a novel strategy for kidney protection while enhancing chemotherapeutic efficacy.