Dabigatran mitigates cisplatin-mediated nephrotoxicity through down regulation of thrombin pathway,Journal of Advanced Research

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Dabigatran mitigates cisplatin-mediated nephrotoxicity through down regulation of thrombin pathway
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2021-01-05 , DOI: 10.1016/j.jare.2020.12.014
Mohamed Gamal El-Din Ewees ₁ , Mohamed Sadek Abdel-Bakky _{2,

3} , Asmaa Mostafa Ahmed Bayoumi ₄ , Ali Ahmed Abo-Saif ₅ , Waleed Mohammad Altowayan ₆ , Khalid Saad Alharbi ₇ , Basim Anwar Shehata Messiha ₈

Affiliation

Introduction

Cisplatin (CDDP) nephrotoxicity is one of the most significant complications limiting its use in cancer therapy.

Objectives

This study investigated the pivotal role played by thrombin in CDDP-mediated nephrotoxicity. This work also aimed to clarify the possible preventive effect of Dabigatran (Dab), a direct thrombin inhibitor, on CDDP nephrotoxicity.

Methods

Animals were grouped as follow; normal control group, CDDP nephrotoxicity group, CDDP + Dab 15, and CDDP + Dab 25 groups. Four days following CDDP administration, blood and urine samples were collected to evaluate renal function. Moreover, tissue samples were collected from the kidney to determine apoptosis markers, oxidative stress and histopathological evaluation. An immunofluorescence analysis of tissue factor (TF), thrombin, protease-activated receptor-2 (PAR2), fibrin, pERK1/2 and P53 proteins expression was also performed.

Results

Thrombin, pERK, cleaved caspase-3, and oxidative stress markers were significantly elevated in CDDP-treated group. However, pretreatment of animals with either low or high doses of Dab significantly improved kidney function and decreased oxidative stress and apoptotic markers.

Conclusion

We conclude that thrombin is an important factor in the pathogenesis of CDDP kidney toxicity via activation of ERK1/2, P53 and caspase-3 pathway, which can be effectively blocked by Dab.

中文翻译：

达比加群通过下调凝血酶途径减轻顺铂介导的肾毒性

介绍

顺铂 (CDDP) 肾毒性是限制其在癌症治疗中使用的最重要的并发症之一。

目标

该研究调查了凝血酶在 CDDP 介导的肾毒性中所起的关键作用。这项工作还旨在阐明达比加群 (Dab)（一种直接凝血酶抑制剂）对 CDDP 肾毒性的可能预防作用。

方法

动物分组如下；正常对照组、CDDP肾毒性组、CDDP+Dab 15和CDDP+Dab 25组。CDDP 给药后四天，收集血液和尿液样本以评估肾功能。此外，从肾脏收集组织样本以确定细胞凋亡标志物、氧化应激和组织病理学评估。还进行了组织因子 (TF)、凝血酶、蛋白酶激活受体 2 (PAR2)、纤维蛋白、pERK1/2 和 P53 蛋白表达的免疫荧光分析。