Dabigatran mitigates cisplatin-mediated nephrotoxicity through down regulation of thrombin pathway

Journal of Advanced Research

Mohamed Sadek Abdel-Bakky¹  Ali Ahmed Abo-Saif²  Waleed Mohammad Altowayan³  Asmaa Mostafa Ahmed Bayoumi⁴  Mohamed Gamal El-Din Ewees⁵  Khalid Saad Alharbi⁶  Basim Anwar Shehata Messiha⁷ 

[1] Corresponding author.;Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt;Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim, Saudi Arabia;Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt;Department of Pharmacology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt;Department of Pharmacy Practice, College of Pharmacy, Qassim University, Qassim, Saudi Arabia;

关键词: Cisplatin;    Dabigatran;    Thrombin;    pERK1/2;    PAR2;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown