Lv Daoyuan, Zhou Qin, Xia Yue, You Xu, Zhao Zhihong, Li Yongqiang, Zou Hequn
Southern Medical University, Guangzhou, China.
Department of Nephrology, Institution of Urology and Nephrology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Kidney Blood Press Res. 2018;43(1):191-205. doi: 10.1159/000487501. Epub 2018 Feb 16.
BACKGROUND/AIMS: Chronic renal allograft dysfunction (CRAD) is a leading cause of long-term renal allograft loss. Oxidative stress may account for the nonspecific interstitial fibrosis and tubular atrophy that occur in CRAD. An antioxidant intervention via Nrf2 signaling pathway activation might be a promising therapy for some kidney diseases. The present paper investigates whether there is an association between oxidative stress alleviation via sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation and CRAD improvement.
F344 rat kidneys were orthotopically transplanted into Lewis rat recipients to establish CRAD models. Sulforaphane was administered at 1.5 mg/kg intraperitoneally once daily. Renal function and 24-hour urinary protein were monitored for variations for 24 weeks after transplantation. After 24 weeks, renal histopathology was evaluated according to the Banff criteria after hematoxylin and eosin, Masson's trichrome and periodic acid-Schiff stainings. Additionally, intrarenal oxidative stress was assessed by the indicators malondialdehyde, 8-isoprostane, oxidized-low density lipoprotein and 8-hydroxy-2'-deoxyguanosine, as well as the activity levels of the antioxidant enzymes total superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and γ-glutamylcysteine synthetase. Nrf2, HO-1 and NQO-1 expression levels were determined via immunohistochemical and Western blot analyses.
The sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation, as demonstrated by immunohistochemical and Western blot analyses, delayed the progression of serum creatinine and blood urea nitrogen, particularly lowering the 24-hour urinary protein levels of CRAD. The semi-quantified histopathological changes were also alleviated. Evidence of oxidative stress alleviation, as indicated by a concurrent decrease in the indicators and sustained levels of antioxidant enzymes activity, was found in the renal allografts after sulforaphane intervention.
Oxidative stress alleviation caused by continuous sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation is associated with functional and morphological improvements of CRAD.
背景/目的：慢性肾移植功能障碍（CRAD）是导致肾移植长期失功的主要原因。氧化应激可能是CRAD中出现的非特异性间质纤维化和肾小管萎缩的原因。通过激活Nrf2信号通路进行抗氧化干预可能是治疗某些肾脏疾病的一种有前景的疗法。本文研究通过萝卜硫素诱导的Nrf2 - HO - 1/NQO - 1信号通路激活减轻氧化应激与改善CRAD之间是否存在关联。
将F344大鼠肾脏原位移植到Lewis大鼠受体中以建立CRAD模型。萝卜硫素以1.5mg/kg的剂量腹腔注射，每日一次。移植后24周监测肾功能和24小时尿蛋白的变化。24周后，苏木精-伊红、Masson三色和过碘酸-希夫染色后，根据Banff标准评估肾脏组织病理学。此外，通过丙二醛、8-异前列腺素、氧化型低密度脂蛋白和8-羟基-2'-脱氧鸟苷指标以及抗氧化酶总超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶、谷胱甘肽还原酶和γ-谷氨酰半胱氨酸合成酶的活性水平评估肾内氧化应激。通过免疫组织化学和蛋白质印迹分析确定Nrf2、HO - 1和NQO - 1的表达水平。
免疫组织化学和蛋白质印迹分析表明，萝卜硫素诱导的Nrf2 - HO - 1/NQO - 1信号通路激活延缓了血清肌酐和血尿素氮的进展，特别是降低了CRAD的24小时尿蛋白水平。半定量组织病理学变化也得到缓解。萝卜硫素干预后，在肾移植中发现氧化应激减轻的证据，表现为指标同时下降和抗氧化酶活性水平持续稳定。
持续的萝卜硫素诱导Nrf2 - HO - 1/NQO - 1信号通路激活所导致的氧化应激减轻与CRAD的功能和形态学改善相关。
