Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea.
Department of Immunology, School of Medicine, Catholic University of Daegu, Daegu 42472, Republic of Korea.
Mediators Inflamm. 2017;2017:4139439. doi: 10.1155/2017/4139439. Epub 2017 Nov 28.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used antihyperglycemic agents for the treatment of type 2 diabetes mellitus. Recently, the pleiotropic actions of DPP-4 inhibitors have drawn much attention. In the present study, we aimed to examine whether gemigliptin, a recently developed DPP-4 inhibitor, could protect against cisplatin-induced nephrotoxicity. We showed that pretreatment with gemigliptin attenuated cisplatin-induced renal dysfunction, as shown by analysis of plasma creatinine levels and blood urea nitrogen and histological damage. Elevated plasma levels of active glucagon-like peptide-1 were observed in gemigliptin-pretreated mice after cisplatin treatment, compared to that in cisplatin alone-treated mice. Gemigliptin attenuated cisplatin-induced apoptotic cell death, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Western blot analysis in the kidneys. Gemigliptin also decreased the plasma levels of tumor necrosis factor- and monocyte chemoattractant protein-1 and attenuated nuclear staining of nuclear factor kappa-B p65 in the kidneys. In addition, gemigliptin increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) in the kidneys of cisplatin-treated mice. Taken together, these results suggest that pretreatment with gemigliptin protects against cisplatin-induced nephrotoxicity in mice, possibly via inhibition of apoptotic cell death and inflammatory responses through induction of HO-1 and NQO1 expression.
二肽基肽酶-4（DPP-4）抑制剂是广泛用于治疗 2 型糖尿病的抗高血糖药物。最近，DPP-4 抑制剂的多效作用引起了广泛关注。在本研究中，我们旨在研究新型 DPP-4 抑制剂 gemigliptin 是否可以预防顺铂诱导的肾毒性。我们发现，gemigliptin 预处理可减轻顺铂引起的肾功能障碍，表现为血浆肌酐和血尿素氮水平以及组织学损伤分析。与单独用顺铂处理的小鼠相比，在用 gemigliptin 预处理的小鼠中，观察到血浆中活性胰高血糖素样肽-1 的水平升高。Gemigliptin 通过末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记和 Western blot 分析减轻了肾脏中的顺铂诱导的细胞凋亡。Gemigliptin 还降低了血浆中肿瘤坏死因子-α和单核细胞趋化蛋白-1 的水平，并减轻了肾脏中核因子κB p65 的核染色。此外，gemigliptin 增加了顺铂处理的小鼠肾脏中血红素加氧酶-1（HO-1）和 NAD（P）H：醌氧化还原酶 1（NQO1）的蛋白表达。综上所述，这些结果表明，gemigliptin 预处理可预防顺铂诱导的小鼠肾毒性，可能通过抑制细胞凋亡和炎症反应，诱导 HO-1 和 NQO1 的表达。
