Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
Oxid Med Cell Longev. 2022 Jun 9;2022:3328623. doi: 10.1155/2022/3328623. eCollection 2022.
Paraquat (PQ) is a widely used herbicide but can be lethal to humans. The kidney is vital for PQ elimination; therefore, explorations for therapeutic approaches for PQ-induced acute kidney injury (AKI) are of great significance. Here, the effects of a natural bioactive polyphenol isorhapontigenin (ISO) on PQ-AKI were investigated. experiments carried out in PQ-intoxicated rat renal tubular epithelial cells (NRK-52E) showed that ISO treatment inhibited PQ-induced cell apoptosis and oxidative stress, which was evidenced by the decreased proapoptotic proteins [cleaved caspase 3/9 and poly (ADP-ribose) polymerase (PARP)], the reduced oxidative stress indicators [reactive oxygen species (ROS), malondialdehyde (MDA), and lactate dehydrogenase (LDH) leakage], and the increased antioxidants [superoxide dismutase (SOD), nuclear factor E2-related factor 2 (NRF2), and oxygenase-1 (HO-1)]. Furthermore, 50 mg/kg ISO pretreatment before PQ administration significantly attenuated PQ-AKI in rats, as manifested by the improved renal tubule damage, the reduced serum and urine markers of kidney injury, and the inhibited cell apoptosis and oxidative stress in the renal cortex. Furthermore, expression of sex-determining region Y box 9 (SOX9) and Toll-interacting protein (TOLLIP) in NRK-52E cells and the renal cortex was significantly upregulated after ISO treatment. Overexpression of SOX9 increased TOLLIP transcription and attenuated PQ-induced apoptosis and oxidative stress, whereas knockdown of SOX9 impaired the protective effects of ISO on NRK-52E cells against PQ toxicity. In conclusion, the present study demonstrated that ISO modulated SOX9/TOLLIP expression to attenuate cell apoptosis and oxidative stress in PQ-AKI, suggesting the potential of ISO in treating PQ-poisoned patients.
百草枯（PQ）是一种广泛使用的除草剂，但对人类却是致命的。肾脏对于 PQ 的消除至关重要；因此，探索治疗 PQ 诱导的急性肾损伤（AKI）的方法具有重要意义。在这里，研究了一种天然生物活性多酚异甘草素（ISO）对 PQ-AKI 的影响。在 PQ 中毒的大鼠肾小管上皮细胞（NRK-52E）中进行的实验表明，ISO 处理抑制了 PQ 诱导的细胞凋亡和氧化应激，这表现在促凋亡蛋白 [裂解的 caspase 3/9 和多聚（ADP-核糖）聚合酶（PARP）]减少、氧化应激指标 [活性氧（ROS）、丙二醛（MDA）和乳酸脱氢酶（LDH）漏出]减少以及抗氧化剂 [超氧化物歧化酶（SOD）、核因子 E2 相关因子 2（NRF2）和氧化酶-1（HO-1）]增加。此外，PQ 给药前 50mg/kg ISO 预处理显著减轻了大鼠的 PQ-AKI，表现为肾小管损伤改善，血清和尿液肾损伤标志物减少，以及肾皮质细胞凋亡和氧化应激抑制。此外，ISO 处理后，NRK-52E 细胞和肾皮质中的性别决定区 Y 框 9（SOX9）和 Toll 相互作用蛋白（TOLLIP）的表达明显上调。SOX9 的过表达增加了 TOLLIP 的转录，并减轻了 PQ 诱导的细胞凋亡和氧化应激，而 SOX9 的敲低则削弱了 ISO 对 NRK-52E 细胞对抗 PQ 毒性的保护作用。总之，本研究表明 ISO 通过调节 SOX9/TOLLIP 表达来减轻 PQ-AKI 中的细胞凋亡和氧化应激，提示 ISO 治疗 PQ 中毒患者的潜力。
