山奈酚对动物模型中他克莫司诱导的肾毒性及钙调神经磷酸酶B1表达水平的影响

Effect of Kaempferol on Tacrolimus-Induced Nephrotoxicity and Calcineurin B1 Expression Level in Animal Model.

作者信息

Ali Ahmed Shaker, Almalki Abdullah Saddah, Alharthy Basma Tarek

机构信息

Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt.

出版信息

J Exp Pharmacol. 2020 Oct 28;12:397-407. doi: 10.2147/JEP.S265359. eCollection 2020.

DOI:10.2147/JEP.S265359

PMID:33149706

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7604448/

Abstract

BACKGROUND

The kidneys are considered one of the most susceptible organs for adverse drug effects, particularly in post-transplant conditions. Tacrolimus (FK506), a calcineurin inhibitor immunosuppressant, is an essential component in the transplantation regimen. Despite that, nephrotoxicity is a severe drawback for its chronic utilization, where oxidative stress might be implicated. Kaempferol (KMF) is a natural flavonoid that has many adaptable biological activities, including antioxidant action.

OBJECTIVE

Exploring the KMF protective effect on FK506-induced nephrotoxicity and the underlying role of calcineurin B1.

METHODS

Twenty-four male albino-Wistar rats were randomly divided into three equal groups. The control group received solvents: propylene glycol, i.p. and 0.5% carboxymethyl cellulose, PO; FK506 group was injected with FK506 (0.6 mg/kg, i.p.), and FK506+KMF group was given FK506 (0.6 mg/kg, i.p.) and KMF (10 mg/kg, PO). The treatment regimen for all groups was once daily for 30 days. ELISA technique applied for measuring FK506 trough level and nephrotoxicity biomarkers in serum (cystatin C and urea) on days 15 and 30, and in kidney tissue homogenate (MDA and calcineurin B1) on day 30.

RESULTS

In FK506-treated rats, the FK506 trough level was 7.84 ± 1.31 ug/l on day 15 and 9.54 ± 1.45 ug/l on day 30. FK506 use has significantly (<0.01) increased biomarkers levels of cystatin C (325% and 477%), urea (177% and 245%), MDA (1253%), except calcineurin B1 that has decreased (97%). The KMF combination has resulted in a significant reduction in the FK506 trough level by day 30 (6.79 ± 1.35 ug/l, <0.01). KMF has significantly ameliorated the levels of cystatin C (46% and 73%, <0.001), urea (38% and 68%, 0.001), MDA (75%, <0.001), and calcineurin B1 (1833%, <0.05).

CONCLUSION

Oxidative stress and calcineurin B1 are contributing factors in FK506-induced nephrotoxicity. Hence, inhibition of calcineurin enzyme is not limited to the immune cells. KMF could be a novel nephroprotective antioxidant.

摘要

背景

肾脏被认为是最易受到药物不良反应影响的器官之一，尤其是在移植后的情况下。他克莫司（FK506）是一种钙调神经磷酸酶抑制剂免疫抑制剂，是移植方案中的重要组成部分。尽管如此，肾毒性是其长期使用的严重缺点，其中氧化应激可能与之相关。山奈酚（KMF）是一种天然黄酮类化合物，具有许多适应性生物学活性，包括抗氧化作用。

目的

探讨KMF对FK506诱导的肾毒性的保护作用以及钙调神经磷酸酶B1的潜在作用。

方法

将24只雄性白化Wistar大鼠随机分为三组，每组数量相等。对照组接受溶剂：腹腔注射丙二醇和口服0.5%羧甲基纤维素；FK506组腹腔注射FK506（0.6mg/kg），FK506+KMF组腹腔注射FK506（0.6mg/kg）并口服KMF（10mg/kg）。所有组的治疗方案均为每日一次，持续30天。采用ELISA技术在第15天和第30天测量血清（胱抑素C和尿素）中FK506谷浓度和肾毒性生物标志物，在第30天测量肾组织匀浆（丙二醛和钙调神经磷酸酶B1）中的相关指标。

结果

在接受FK506治疗的大鼠中，第15天FK506谷浓度为7.84±1.31μg/l，第30天为9.54±1.45μg/l。使用FK506显著（<0.01）增加了胱抑素C（分别增加325%和477%）、尿素（分别增加177%和245%）、丙二醛（增加1253%）的生物标志物水平，但钙调神经磷酸酶B1水平降低（降低97%）。到第30天，KMF联合用药使FK506谷浓度显著降低（6.79±1.35μg/l，<0.01）。KMF显著改善了胱抑素C（分别降低46%和73%，<0.001）、尿素（分别降低38%和68%，0.001）、丙二醛（降低75%，<0.001）和钙调神经磷酸酶B1（增加1833%，<0.05）的水平。