Effect of Kaempferol on Tacrolimus-Induced Nephrotoxicity and Calcineurin B1 Expression Level in Animal Model.
Effect of Kaempferol on Tacrolimus-Induced Nephrotoxicity and Calcineurin B1 Expression Level in Animal Model.
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DOI：
10.2147/jep.s265359
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发表时间：
2020
影响因子：
--
通讯作者：
Alharthy BT
中科院分区：
文献类型：
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作者：
Ali AS;Almalki AS;Alharthy BT
肾脏被认为是最易受药物不良反应影响的器官之一，特别是在移植后条件下。他克莫司（FK 506），钙调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一个严重缺点，其中可能涉及氧化应激。山奈酚（KMF）是一种天然黄酮类化合物，具有多种适应性生物活性，包括抗氧化作用。探索KMF对FK 506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。24只雄性白化Wistar大鼠随机分为3组。对照组接受溶剂：丙二醇，腹腔注射和0.5%羧甲基纤维素，PO; FK 506组注射FK 506（0.6 mg/kg，腹腔注射），FK 506 +KMF组给予FK 506（0.6mg/kg，i. p.）和KMF（10mg/kg，PO）。所有组的治疗方案均为每日一次，持续30天。采用ELISA技术测量第15天和第30天血清（半胱氨酸蛋白酶抑制剂C和尿素）以及第30天肾组织匀浆（MDA和钙调神经磷酸酶B1）中的FK 506谷浓度和肾毒性生物标志物。在FK 506给药大鼠中，第15天和第30天的FK 506谷浓度分别为7.84 ± 1.31 ug/l和9.54 ± 1.45 ug/l。FK 506治疗组血清胱抑素C（325%和477%）、尿素（177%和245%）、MDA（1253%）水平显著升高（P<0.01），钙调神经磷酸酶B1水平显著降低（97%）。KMF联合给药导致第30天FK 506谷浓度显著降低（6.79 ± 1.35 ug/l，P<0.01）。KMF能显著降低CystatinC（46%和73%，P<0.001）、尿素（38%和68%，P<0.001）、MDA（75%，P<0.001）和钙调神经磷酸酶B1（1833%，P<0.05）水平。氧化应激和钙调神经磷酸酶B1是FK 506诱导肾毒性的促成因素。因此，钙调磷酸酶的抑制不限于免疫细胞。KMF可能是一种新的肾保护性抗氧化剂。
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. Exploring the KMF protective effect on FK506-induced nephrotoxicity and the underlying role of calcineurin B1. 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. 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 (P<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, P<0.01). KMF has significantly ameliorated the levels of cystatin C (46% and 73%, P<0.001), urea (38% and 68%, P<0.001), MDA (75%, P<0.001), and calcineurin B1 (1833%, P<0.05). 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.