Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Clinical Poison Center, Kidney Research Center, And Center for Tissue Engineering, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Free Radic Biol Med. 2022 Oct;191:249-260. doi: 10.1016/j.freeradbiomed.2022.08.031. Epub 2022 Aug 27.
Although paraquat (PQ) induces oxidative damage and inflammatory responses in the lungs, the mechanism underlying PQ-induced acute kidney injury in patients is unclear. Immunosuppressive therapy with glucocorticoids and the immunosuppressant cyclophosphamide (CP) has been employed to treat patients with PQ poisoning. This study examined whether PQ could concurrently cause renal injury, inflammatory responses, and oxidative damage in the kidneys, and whether CP and dexamethasone (DEX) could suppress PQ-induced alterations. Mice were assigned to eight groups: Control, PQ, DEX, PQ plus DEX, CP, PQ plus CP, DEX plus CP, and PQ plus DEX with CP. DEX, CP, and DEX plus CP reversed PQ-induced renal injury, as indicated by urinary albumin-to-creatinine ratios and urea nitrogen levels in serum. The treatments also attenuated PQ-induced renal infiltration of leukocytes and macrophages and induction of the Il6, Tnf, Icam, Cxcl2, Tlr4, and Tlr9 genes encoding the inflammatory mediators in the kidneys. However, DEX only partially suppressed the macrophage infiltration, whereas DEX plus CP provided stronger protection than DEX or CP alone for the induction of Il6 and Cxcl2. Moreover, through the detection of F-isoprostanes (F-IsoPs) and isofurans in the kidneys and lungs and F-IsoPs in the plasma and urine, the therapies were found to suppress PQ-induced lipid peroxidation, although DEX was less effective. Finally, PQ decreased ubiquinol-9:ubiquinone-9 ratios in the kidneys. This effect of PQ was not found under CP treatment, but the ratio was lower than that of the control group. Our findings suggest that the suppression of PQ-induced inflammatory responses by DEX and CP in the kidneys can mitigate oxidative damage and acute kidney injury.
尽管百草枯（PQ）会在肺部引起氧化损伤和炎症反应，但目前尚不清楚 PQ 导致患者急性肾损伤的机制。免疫抑制剂糖皮质激素和免疫抑制剂环磷酰胺（CP）已被用于治疗百草枯中毒患者。本研究旨在探讨 PQ 是否会同时引起肾脏损伤、炎症反应和氧化损伤，以及 CP 和地塞米松（DEX）是否可以抑制 PQ 诱导的改变。将小鼠分为八组：对照组、PQ 组、DEX 组、PQ 加 DEX 组、CP 组、PQ 加 CP 组、DEX 加 CP 组和 PQ 加 DEX 加 CP 组。DEX、CP 和 DEX 加 CP 逆转了 PQ 引起的肾损伤，表现为尿白蛋白与肌酐比值和血清尿素氮水平升高。这些治疗还减轻了 PQ 诱导的肾脏白细胞和巨噬细胞浸润以及炎症介质基因 Il6、Tnf、Icam、Cxcl2、Tlr4 和 Tlr9 的诱导。然而，DEX 仅部分抑制了巨噬细胞浸润，而 DEX 加 CP 对 Il6 和 Cxcl2 的诱导提供了比 DEX 或 CP 单独更强的保护。此外，通过检测肾脏和肺中的 F-异前列腺素（F-IsoPs）和异呋喃以及血浆和尿液中的 F-IsoPs，发现这些治疗方法抑制了 PQ 诱导的脂质过氧化，尽管 DEX 的效果较弱。最后，PQ 降低了肾脏中的泛醇-9：泛醌-9 比值。在 CP 治疗下未发现 PQ 对该比值的影响，但该比值低于对照组。我们的研究结果表明，DEX 和 CP 在肾脏中抑制 PQ 诱导的炎症反应可以减轻氧化损伤和急性肾损伤。
