Chatterjee Prodyot K, Yeboah Michael M, Solanki Malvika H, Kumar Gopal, Xue Xiangying, Pavlov Valentin A, Al-Abed Yousef, Metz Christine N
Center for Biomedical Sciences, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States of America.
Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, United States of America.
PLoS One. 2017 Nov 30;12(11):e0188797. doi: 10.1371/journal.pone.0188797. eCollection 2017.
Acute kidney injury (AKI) is the most common side effect of cisplatin, a widely used chemotherapy drug. Although AKI occurs in up to one third of cancer patients receiving cisplatin, effective renal protective strategies are lacking. Cisplatin targets renal proximal tubular epithelial cells leading to inflammation, reactive oxygen species, tubular cell injury, and eventually cell death. The cholinergic anti-inflammatory pathway is a vagus nerve-mediated reflex that suppresses inflammation via α7 nicotinic acetylcholine receptors (α7nAChRs). Our previous studies demonstrated the renoprotective and anti-inflammatory effects of cholinergic agonists, including GTS-21. Therefore, we examined the effect of GTS-21 on cisplatin-induced AKI. Male C57BL/6 mice received either saline or GTS-21 (4mg/kg, i.p.) twice daily for 4 days before cisplatin and treatment continued through euthanasia; 3 days post-cisplatin mice were euthanized and analyzed for markers of renal injury. GTS-21 significantly reduced cisplatin-induced renal dysfunction and injury (p<0.05). GTS-21 significantly attenuated renal Ptgs2/COX-2 mRNA and IL-6, IL-1β, and CXCL1 protein expression, as well as neutrophil infiltration after cisplatin. GTS-21 blunted cisplatin-induced renal ERK1/2 activation, as well as renal ATP depletion and apoptosis (p<0.05). GTS-21 suppressed the expression of CTR1, a cisplatin influx transporter and enhanced the expression of cisplatin efflux transporters MRP2, MRP4, and MRP6 (p<0.05). Using breast, colon, and lung cancer cell lines we showed that GTS-21 did not inhibit cisplatin's tumor cell killing activity. GTS-21 protects against cisplatin-AKI by attenuating renal inflammation, ATP depletion and apoptosis, as well as by decreasing renal cisplatin influx and increasing efflux, without impairing cisplatin-mediated tumor cell killing. Our results support further exploring the cholinergic anti-inflammatory pathway for preventing cisplatin-induced AKI.
急性肾损伤（AKI）是广泛使用的化疗药物顺铂最常见的副作用。尽管在接受顺铂治疗的癌症患者中，高达三分之一会发生AKI，但目前仍缺乏有效的肾脏保护策略。顺铂作用于肾近端小管上皮细胞，导致炎症、活性氧生成、肾小管细胞损伤，最终导致细胞死亡。胆碱能抗炎通路是一种迷走神经介导的反射，通过α7烟碱型乙酰胆碱受体（α7nAChRs）抑制炎症。我们之前的研究证明了胆碱能激动剂（包括GTS-21）的肾脏保护和抗炎作用。因此，我们研究了GTS-21对顺铂诱导的AKI的影响。雄性C57BL/6小鼠在注射顺铂前4天，每天两次腹腔注射生理盐水或GTS-21（4mg/kg），治疗持续至安乐死；顺铂注射后3天，对小鼠实施安乐死，并分析肾脏损伤标志物。GTS-21显著降低了顺铂诱导的肾功能障碍和损伤（p<0.05）。GTS-21显著减弱了顺铂诱导的肾脏Ptgs2/COX-2 mRNA以及IL-6、IL-1β和CXCL1蛋白表达，以及顺铂注射后的中性粒细胞浸润。GTS-21抑制了顺铂诱导的肾脏ERK1/2激活，以及肾脏ATP消耗和细胞凋亡（p<0.05）。GTS-21抑制了顺铂流入转运体CTR1的表达，并增强了顺铂流出转运体MRP2、MRP4和MRP6的表达（p<0.05）。使用乳腺癌、结肠癌和肺癌细胞系，我们发现GTS-21不会抑制顺铂的肿瘤细胞杀伤活性。GTS-21通过减轻肾脏炎症、ATP消耗和细胞凋亡，以及减少肾脏顺铂流入和增加流出，来预防顺铂诱导的AKI，而不会损害顺铂介导的肿瘤细胞杀伤作用。我们的结果支持进一步探索胆碱能抗炎通路以预防顺铂诱导的AKI。
