Feng Yuying, Huang Rongshuang, Guo Fan, Liang Yan, Xiang Jin, Lei Song, Shi Min, Li Lingzhi, Liu Jing, Feng Yanhuan, Ma Liang, Fu Ping
Division of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, China.
Core Facility of West China Hospital, West China Hospital of Sichuan University, Chengdu, China.
Front Pharmacol. 2018 Mar 26;9:274. doi: 10.3389/fphar.2018.00274. eCollection 2018.
Histone deacetylase 6 (HDAC6) contributed to the pathogenesis of rhabdomyolysis-induced acute kidney injury (AKI) and selective inhibition of HDAC6 activity may be a promising strategy for the treatment of AKI. Compound 23BB as a highly selective HDAC6 inhibitor was designed, synthesized by our lab and exhibited therapeutic potential in various cancer models with good safety. However, it remained unknown whether 23BB as a drug candidate could offer renal protective effect against rhabdomyolysis-induced AKI. In the present study, we investigated the effect of 23BB in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe AKI as indicated by acute renal dysfunction and histologic changes, accompanied by increased HDAC6 expression in the cytoplasm of tubular epithelial cells. Pharmacological inhibition of HDAC6 by 23BB pretreatment significantly reduced serum creatinine and serum blood urea nitrogen (BUN) levels as well as attenuated renal tubular damage in GL-injured kidneys. HDAC6 inhibition also resulted in reduced TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells, suppressed BAX, BAK, cleaved caspase-3 levels, and preserved Bcl-2 expression, indicating that 23BB exerted potent renoprotective effects by the regulation of tubular cell apoptosis. Moreover, GL-induced kidney injury triggered multiple signal mediators of endoplasmic reticulum (ER) stress including GRP78, CHOP, IRE1α, p-eIF2α, ATF4, XBP1, p-JNK, and caspase-12. Oral administration of 23BB improved above-mentioned responses in injured kidney tissues and suggested that 23BB modulated tubular cell apoptosis via the inactivation of ER stress. Overall, these data highlighted that renal protection of novel HDAC6 inhibitor 23BB is substantiated by the reduction of ER stress-mediated apoptosis in tubular epithelial cells of rhabdomyolysis-induced AKI.
组蛋白脱乙酰酶6（HDAC6）促成了横纹肌溶解诱导的急性肾损伤（AKI）的发病机制，选择性抑制HDAC6活性可能是治疗AKI的一种有前景的策略。化合物23BB作为一种高度选择性的HDAC6抑制剂，由我们实验室设计、合成，并在各种癌症模型中显示出治疗潜力且安全性良好。然而，作为候选药物的23BB是否能对横纹肌溶解诱导的AKI提供肾脏保护作用仍不清楚。在本研究中，我们研究了23BB在甘油（GL）注射诱导的横纹肌溶解小鼠模型中的作用。注射GL后，小鼠出现严重的AKI，表现为急性肾功能障碍和组织学变化，同时肾小管上皮细胞胞质中HDAC6表达增加。23BB预处理对HDAC6的药理学抑制显著降低了血清肌酐和血清尿素氮（BUN）水平，并减轻了GL损伤肾脏中的肾小管损伤。HDAC6抑制还导致末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）阳性肾小管细胞减少，抑制BAX、BAK、裂解的半胱天冬酶-3水平，并维持Bcl-2表达，表明23BB通过调节肾小管细胞凋亡发挥强大的肾脏保护作用。此外，GL诱导的肾损伤触发了内质网（ER）应激的多种信号介质，包括GRP78、CHOP、IRE1α、p-eIF2α、ATF4、XBP1、p-JNK和半胱天冬酶-12。口服23BB改善了受损肾组织中的上述反应，并表明23BB通过使ER应激失活来调节肾小管细胞凋亡。总体而言，这些数据突出表明，新型HDAC6抑制剂23BB的肾脏保护作用是通过减少横纹肌溶解诱导的AKI肾小管上皮细胞中ER应激介导的凋亡来证实的。
