Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York.
Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York.
Am J Physiol Renal Physiol. 2019 Sep 1;317(3):F743-F756. doi: 10.1152/ajprenal.00182.2019. Epub 2019 Jul 17.
Acute kidney injury (AKI) due to renal ischemia-reperfusion (I/R) is a major clinical problem without effective therapy. Ginger is one of the most widely consumed spices in the world, and 6-shogaol, a major ginger metabolite, has anti-inflammatory effects in neuronal and epithelial cells. Here, we demonstrate our novel findings that 6-shogaol treatment protected against renal I/R injury with decreased plasma creatinine, blood urea nitrogen, and kidney neutrophil gelatinase-associated lipocalin mRNA synthesis compared with vehicle-treated mice subjected to renal I/R. Additionally, 6-shogaol treatment reduced kidney inflammation (decreased proinflammatory cytokine and chemokine synthesis as well as neutrophil infiltration) and apoptosis (decreased TUNEL-positive renal tubular cells) compared with vehicle-treated mice subjected to renal I/R. In cultured human and mouse kidney proximal tubule cells, 6-shogaol significantly attenuated TNF-α-induced inflammatory cytokine and chemokine mRNA synthesis. Mechanistically, 6-shogaol significantly attenuated TNF-α-induced NF-κB activation in human renal proximal tubule cells by reducing IKKαβ/IκBα phosphorylation. Furthermore, 6-shogaol induced a cytoprotective chaperone heme oxygenase (HO)-1 via p38 MAPK activation in vitro and in vivo. Consistent with these findings, pretreatment with the HO-1 inhibitor zinc protoporphyrin IX completely prevented 6-shogaol-mediated protection against ischemic AKI in mice. Taken together, our study showed that 6-shogaol protects against ischemic AKI by attenuating NF-κB activation and inducing HO-1 expression. 6-Shogaol may provide a potential therapy for ischemic AKI during the perioperative period.
肾缺血再灌注（I/R）引起的急性肾损伤（AKI）是一种重大的临床问题，目前尚无有效的治疗方法。生姜是世界上消费最广泛的香料之一，其主要代谢物 6-姜辣素在神经元和上皮细胞中具有抗炎作用。在这里，我们展示了我们的新发现，即与接受肾 I/R 的 vehicle 处理的小鼠相比，6-姜辣素处理可通过降低血浆肌酐、血尿素氮和肾脏中性粒细胞明胶酶相关脂质运载蛋白 mRNA 的合成来保护免受肾 I/R 损伤。此外，与接受肾 I/R 的 vehicle 处理的小鼠相比，6-姜辣素处理可减少肾脏炎症（减少促炎细胞因子和趋化因子的合成以及中性粒细胞浸润）和凋亡（减少 TUNEL 阳性肾小管细胞）。在培养的人源和鼠源肾近端小管细胞中，6-姜辣素显著减弱了 TNF-α诱导的炎症细胞因子和趋化因子 mRNA 的合成。在机制上，6-姜辣素通过减少 IKKαβ/IκBα磷酸化显著减弱了 TNF-α诱导的人肾近端小管细胞中 NF-κB 的激活。此外，6-姜辣素通过激活 p38 MAPK 在体外和体内诱导保护性伴侣血红素加氧酶（HO）-1。与这些发现一致，HO-1 抑制剂锌原卟啉 IX 的预处理完全阻止了 6-姜辣素介导的对小鼠缺血性 AKI 的保护作用。总之，我们的研究表明，6-姜辣素通过抑制 NF-κB 激活和诱导 HO-1 表达来保护缺血性 AKI。6-姜辣素可能为围手术期缺血性 AKI 提供一种潜在的治疗方法。
