Dipeptidyl peptidase-4 inhibitor teneligliptin accelerates recovery from cisplatin-induced acute kidney injury by attenuating inflammation and promoting tubular regeneration
Dipeptidyl peptidase-4 inhibitor teneligliptin accelerates recovery from cisplatin-induced acute kidney injury by attenuating inflammation and promoting tubular regeneration
复制标题
DOI：
10.1093/ndt/gfy397
复制
发表时间：
2019-10-01
影响因子：
6.1
通讯作者：
Anders, Hans Joachim
中科院分区：
文献类型：
--
作者：
Iwakura, Takamasa;Zhao, Zhibo;Anders, Hans Joachim
背景顺铂是一种有效的化疗药物。然而，急性肾损伤（阿基）和随后的肾功能下降限制了其使用。据报道，二肽基肽酶-4（DPP-4）抑制剂在一些体内模型中可减轻肾损伤，但阿基后肾小管恢复的作用机制仍处于推测状态。我们假设DPP-4抑制剂teneliglitazone（TG）可以促进顺铂诱导的AKI后的肾脏恢复。在体内实验中，通过静脉注射5 mg/kg顺铂诱导大鼠阿基。在注射顺铂之前或从注射顺铂后第5天开始每天一次口服给予10 mg/kg TG。在体外实验中，用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四氮唑溴盐（MTT）法、细胞周期分析和细胞计数来评价分离的小鼠肾小管细胞的增殖。MTT法和乳酸脱氢酶（LDH）法检测细胞活力。在体内实验中，我们发现TG减弱顺铂诱导的阿基，并通过促进近端小管存活上皮细胞的增殖来加速损伤后的肾脏恢复。TG还抑制肾内肿瘤坏死因子-α表达，并诱导巨噬细胞向抗炎M2表型极化，两者都间接支持顺铂损伤后肾小管恢复。在体外实验中，TG直接促进原代肾小管上皮细胞的增殖。体外DPP-4底物趋化因子的系统筛选鉴定了CXC趋化因子配体（CXCL）-12作为促进促有丝分裂因子。CXCL 12不仅促进顺铂暴露后的原代肾小管上皮细胞的增殖，而且抑制细胞死亡。CXC趋化因子受体（CXCR）-4拮抗剂可消除TG的增殖作用。DPP-4抑制剂TG可通过抗炎作用和可能通过抑制CXCL 12分解加速肾小管再生和毒性阿基的功能恢复。因此，DPP-4抑制剂可限制顺铂诱导的肾毒性并改善癌症患者的肾功能。
Background. Cisplatin is an effective chemotherapeutic agent. However, acute kidney injury (AKI) and subsequent kidney function decline limits its use. Dipeptidyl peptidase-4 (DPP-4) inhibitor has been reported to attenuate kidney injury in some in vivo models, but the mechanisms-of-action in tubule recovery upon AKI remain speculative. We hypothesized that DPP-4 inhibitor teneligliptin (TG) can facilitate kidney recovery after cisplatin-induced AKI.Methods. In in vivo experiment, AKI was induced in rats by injecting 5 mg/kg of cisplatin intravenously. Oral administration of 10 mg/kg of TG, once a day, was started just before injecting cisplatin or from Day 5 after cisplatin injection. In an in vitro experiment, proliferation of isolated murine tubular cells was evaluated with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and cell counting. Cell viability was analysed by MTT assay or lactate dehydrogenase (LDH) assay.Results. In in vivo experiments, we found that TG attenuates cisplatin-induced AKI and accelerates kidney recovery after the injury by promoting the proliferation of surviving epithelial cells of the proximal tubule. TG also suppressed intrarenal tumour necrosis factor-alpha expression, and induced macrophage polarization towards the anti-inflammatory M2 phenotype, both indirectly endorsing tubule recovery upon cisplatin injury. In in vitro experiments, TG directly accelerated the proliferation of primary tubular epithelial cells. Systematic screening of the DPP-4 substrate chemokines in vitro identified CXC chemokine ligand (CXCL)-12 as a promoted mitogenic factor. CXCL12 not only accelerated proliferation but also inhibited cell death of primary tubular epithelial cells after cisplatin exposure. CXC chemokine receptor (CXCR)-4 antagonism abolished the proliferative effect of TG.Conclusions. The DPP-4 inhibitor TG can accelerate tubule regeneration and functional recovery from toxic AKI via an anti-inflammatory effect and probably via inhibition of CXCL12 breakdown. Hence, DPP-4 inhibitors may limit cisplatin-induced nephrotoxicity and improve kidney function in cancer patients.