Department of Immunology, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea.
Department of Physiology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.
Mediators Inflamm. 2018 Dec 23;2018:6571676. doi: 10.1155/2018/6571676. eCollection 2018.
Caspase-1 is a proinflammatory caspase responsible for the proteolytic conversion of the precursor forms of interleukin-1 to its active form and plays an important role in the pathogenesis of various inflammatory diseases. It was reported that genetic deficiency of caspase-1 prevented cisplatin-induced nephrotoxicity. However, whether pharmacological inhibition of caspase-1 also has a preventive effect against cisplatin-induced kidney injury has not been evaluated. In this study, we examined the effect of Ac-YVAD-cmk, a potent caspase-1-specific inhibitor, on renal function and histology in cisplatin-treated mice and explored its underlying mechanisms. We found that administration of Ac-YVAD-cmk effectively attenuated cisplatin-induced renal dysfunction, as evidenced by reduced plasma levels of blood urea nitrogen and creatinine, and histological abnormalities, such as tubular cell death, dilatation, and cast formation. Administration of Ac-YVAD-cmk inhibited caspase-3 activation as well as caspase-1 activation and attenuated apoptotic cell death, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, in the kidneys of cisplatin-treated mice. Cisplatin-induced G2/M arrest of renal tubular cells was also reduced by caspase-1 inhibition. In addition, administration of Ac-YVAD-cmk reversed increased oxidative stress and depleted antioxidant capacity after cisplatin treatment. Moreover, increased macrophage accumulation and elevated expression of cytokines and chemokines were attenuated by caspase-1 inhibition. Taken together, these results suggest that caspase-1 inhibition by Ac-YVAD-cmk protects against cisplatin-induced nephrotoxicity through inhibition of renal tubular cell apoptosis, oxidative stress, and inflammatory responses. Our findings support the idea that caspase-1 may be a promising pharmacological target for the prevention of cisplatin-induced kidney injury.
Caspase-1 是一种促炎半胱天冬酶，负责前体形式白细胞介素-1 到其活性形式的蛋白水解转化，在各种炎症性疾病的发病机制中发挥重要作用。有报道称，caspase-1 的遗传缺陷可防止顺铂诱导的肾毒性。然而，caspase-1 的药理学抑制是否对顺铂诱导的肾损伤也具有预防作用尚未得到评估。在这项研究中，我们研究了 Ac-YVAD-cmk（一种有效的 caspase-1 特异性抑制剂）对顺铂处理的小鼠肾功能和组织学的影响，并探讨了其潜在机制。我们发现，Ac-YVAD-cmk 的给药可有效减轻顺铂引起的肾功能障碍，表现为血浆血尿素氮和肌酐水平降低，以及组织学异常，如肾小管细胞死亡、扩张和铸型形成。Ac-YVAD-cmk 的给药抑制了 caspase-3 的激活以及 caspase-1 的激活，并通过末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记法减轻了顺铂处理的小鼠肾脏中的细胞凋亡。Caspase-1 的抑制还降低了顺铂诱导的肾小管细胞 G2/M 期阻滞。此外，Ac-YVAD-cmk 的给药逆转了顺铂处理后氧化应激的增加和抗氧化能力的耗竭。此外，caspase-1 的抑制减轻了巨噬细胞的积累和细胞因子和趋化因子表达的增加。总之，这些结果表明，Ac-YVAD-cmk 通过抑制肾小管细胞凋亡、氧化应激和炎症反应来防止顺铂诱导的肾毒性。我们的研究结果支持了 caspase-1 可能是预防顺铂诱导的肾损伤的有前途的药理学靶点的观点。
