环磷酰胺是一种烷基化剂，具有广泛的治疗活性。目前，由于其众多的不良反应，包括肾毒性，其医疗用途受到限制。本研究旨在追踪乳铁蛋白（LF）对环磷酰胺（CP）引起的肾损伤可能具有的肾保护作用的分子机制。为实现我们的目标，我们将Spragw-Dwaly 大鼠口服 LF（300mg/kg）七天，随后注射一次腹腔内的CP（150mg/kg）。在LF治疗下，CP损伤的大鼠中，明显降低了肌酐和血尿素氮（BUN），明显上调了Nrf2/HO-1信号传导，并随之增加了肾脏总抗氧化能力（TAC），降低了肾脏丙二醛（MDA）水平。此外，LF治疗显著降低了CP处理动物中升高的肾脏p-ERK1/2表达、肿瘤坏死因子-α（TNFα）、白细胞介素-6（IL-6）、核因子-kappa B（NF-κB）水平。有趣的是，LF治疗下调了Wnt4/β-泡腾蛋白信号，同时增加了肾素基因表达和血清肾素水平。此外，LF治疗通过抑制GSK-3β表达和调节caspase-3 和 Bcl2 水平，减少了肾组织中的细胞凋亡。肾组织的组织病理检查证实了LF对CP引起的肾损伤的保护作用。本研究发现了LF对CP引起的肾病的肾保护作用，可能是通过抑制ERK1/2/NF-κB和Wnt4/β-泡腾蛋白轨迹，增强klotho表达和Nrf2/HO-1信号传导来介导的。版权所有 © 2023 Elsevier Inc. 发布。

Cyclophosphamide is an alkylating agent with vast arrays of therapeutic activity. Currently, its medical use is limited due to its numerous adverse events, including nephrotoxicity. This study aimed to follow the molecular mechanisms behind the potential renoprotective action of lactoferrin (LF) against cyclophosphamide (CP)-induced renal injury.For fulfillment of our aim, Spragw-Dwaly rats were orally administrated LF (300 mg/kg) for seven consecutive days, followed by a single intraperitoneal injection of CP (150 mg/kg).Treatment of CP-injured rats with LF significantly reduced the elevated creatinine and blood urea nitrogen (BUN), markedly upregulated Nrf2/HO-1 signaling with consequent increase in renal total antioxidant capacity (TAC) and decrease in renal malondialdehyde (MDA) level. Furthermore, LF treatment significantly reduced the elevated renal p-ERK1/2 expression, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), nuclear factor-kappa B (NF-κB) levels in CP-treated animals. Interestingly, LF treatment downregulated Wnt4/β-catenin signaling and increased both renal klotho gene expression and serum klotho level. Furthermore, LF treatment reduced apoptosis in kidney tissue via suppressing GSK-3β expression and modulating caspase-3 and Bcl2 levels. Histopathological examination of kidney tissue confirmed the protective effect of LF against CP-induced renal injury.The present findings document the renoprotective effect of LF against CP-induced nephropathy, which may be mediated via suppressing ERK1/2/ NF-κB and Wnt4/β-catenin trajectories and enhancing klotho expression and Nrf2/HO-1 signaling.Copyright © 2023. Published by Elsevier Inc.