Airik Merlin, Clayton Kacian, Wipf Peter, Airik Rannar
Division of Nephrology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Antioxidants (Basel). 2024 Dec 15;13(12):1534. doi: 10.3390/antiox13121534.
Cisplatin is a commonly used chemotherapeutic agent in the treatment of a wide array of cancers. Due to its active transport into the kidney proximal tubule cells, cisplatin treatment can cause a buildup of this nephrotoxic compound in the kidney, resulting in acute kidney injury (AKI). About 30% of patients receiving cisplatin chemotherapy develop cisplatin-induced AKI. JP4-039 is a mitochondria-targeted reactive oxygen species (ROS) and electron scavenger. Recent studies have shown that JP4-039 mitigates a variety of genotoxic insults in preclinical studies in rodents by suppressing oxidative stress-mediated tissue damage and blocking apoptosis and ferroptosis. However, the benefits of JP4-039 treatment have not been tested in the setting of AKI. In this study, we investigated the potential renoprotective effect of JP4-039 on cisplatin-induced AKI. To address this goal, we treated mice with JP4-039 before or after cisplatin administration and analyzed them for functional and molecular changes in the kidney. JP4-039 co-administration attenuated cisplatin-induced renal dysfunction and histopathological changes. Upregulation of tubular injury markers was also suppressed by JP4-039. Mechanistically, JP4-039 suppressed lipid peroxidation, prevented tissue oxidative stress, and preserved the glutathione levels in cisplatin-injected mice. An increase in cisplatin-induced apoptosis and ferroptosis was also alleviated by the compound. Moreover, JP4-039 inhibited cytokine overproduction in cisplatin-injected mice. Together, our findings demonstrate that JP4-039 is a promising therapeutic agent against cisplatin-induced kidney injury.
顺铂是一种常用于治疗多种癌症的化疗药物。由于其可主动转运至肾近端小管细胞，顺铂治疗可导致这种肾毒性化合物在肾脏中蓄积，从而引发急性肾损伤（AKI）。约30%接受顺铂化疗的患者会发生顺铂诱导的AKI。JP4-039是一种靶向线粒体的活性氧（ROS）和电子清除剂。最近的研究表明，在啮齿动物的临床前研究中，JP4-039通过抑制氧化应激介导的组织损伤以及阻断细胞凋亡和铁死亡，减轻了多种基因毒性损伤。然而，JP4-039治疗的益处尚未在AKI的背景下进行测试。在本研究中，我们调查了JP4-039对顺铂诱导的AKI的潜在肾脏保护作用。为实现这一目标，我们在给予顺铂之前或之后用JP4-039处理小鼠，并分析它们肾脏中的功能和分子变化。联合使用JP4-039可减轻顺铂诱导的肾功能障碍和组织病理学变化。JP4-039还抑制了肾小管损伤标志物的上调。从机制上讲，JP4-039抑制了脂质过氧化，防止了组织氧化应激，并维持了注射顺铂小鼠体内的谷胱甘肽水平。该化合物还减轻了顺铂诱导的细胞凋亡和铁死亡的增加。此外，JP4-039抑制了注射顺铂小鼠体内细胞因子的过度产生。总之，我们的研究结果表明，JP4-039是一种有前景的抗顺铂诱导肾损伤的治疗药物。
