Department of Medicine IV, University Hospital Ludwig-Maximilians-Universität München, Munich, Germany.
Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Nephrol Dial Transplant. 2019 Oct 1;34(10):1669-1680. doi: 10.1093/ndt/gfy397.
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.
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.
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-α 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.
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.
顺铂是一种有效的化疗药物。然而，急性肾损伤（AKI）及其随后的肾功能下降限制了其使用。二肽基肽酶-4（DPP-4）抑制剂已被报道在一些体内模型中减轻肾损伤，但在 AKI 后肾小管恢复的作用机制仍存在推测。我们假设 DPP-4 抑制剂替格列汀（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 5mg/kg 的顺铂在大鼠中诱导 AKI。在注射顺铂前或顺铂注射后第 5 天开始，每天口服 10mg/kg 的 TG。在体外实验中，通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）测定法、细胞周期分析和细胞计数评估分离的鼠肾小管细胞的增殖。通过 MTT 测定法或乳酸脱氢酶（LDH）测定法分析细胞活力。
在体内实验中，我们发现 TG 通过促进近端肾小管存活上皮细胞的增殖来减轻顺铂诱导的 AKI 并加速损伤后的肾脏恢复。TG 还抑制了肾内肿瘤坏死因子-α的表达，并诱导了巨噬细胞向抗炎 M2 表型的极化，这两者都间接促进了顺铂损伤后的肾小管恢复。在体外实验中，TG 直接加速了原代肾小管上皮细胞的增殖。体外系统筛选 DPP-4 底物趋化因子鉴定出 CXC 趋化因子配体（CXCL）-12 作为促有丝分裂因子。CXCL12 不仅加速了增殖，而且在顺铂暴露后还抑制了原代肾小管上皮细胞的死亡。CXC 趋化因子受体（CXCR）-4 拮抗剂消除了 TG 的增殖作用。
DPP-4 抑制剂 TG 可以通过抗炎作用和可能通过抑制 CXCL12 分解来加速有毒 AKI 的肾小管再生和功能恢复。因此，DPP-4 抑制剂可能会限制顺铂引起的肾毒性并改善癌症患者的肾功能。
