Abdel-Bakky Mohamed S, Aldakhili Anas S A, Ali Hussein M, Babiker Ali Y, Alhowail Ahmad H, Mohammed Salman A A
Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
Pharmaceuticals (Basel). 2023 Jun 21;16(7):910. doi: 10.3390/ph16070910.
Acute renal failure (ARF) is a deleterious condition with increased mortality or healthcare costs or dialysis-dependent end-stage renal disease. The study aims to compare prophylaxis with fondaparinux (Fund) vs. treatment with alteplase (Alt) in ameliorating cisplatin (Cis)-induced ARF. Sixty male mice were equally divided randomly into six groups of control, Cis, Alt, and Cis + Alt groups receiving normal saline for 10 days. All four groups except for the control received Cis (30 mg/kg, i.p.) on day 7, and 6 h later, both the Alt groups received Alt (0.9 mg/kg, i.v.). The animal groups Fund and Fund + Cis received Fund (5 mg/kg, i.p.) for 10 days, and the Fund + Cis group on day 7 received Cis. All the animal groups were euthanized 72 h after the Cis dose. The Fund + Cis group showed significantly increased expression levels of platelet count, retinoid X receptor alpha (RXR-α) and phosphorylated Akt (p-Akt) in addition to decreased levels of urea, blood urea nitrogen (BUN), uric acid, white blood cells (WBCs), red blood cells (RBCs), relative kidney body weight, kidney injury score, glucose, prothrombin (PT), A Disintegrin And Metalloproteinases-10 (ADAM10), extracellular matrix deposition, protease-activated receptor 2 (PAR-2), and fibrinogen expression when compared to the Cis-only group. Meanwhile, the Cis + Alt group showed increased caspase-3 expression in addition to decreased levels of urea, BUN, uric acid, WBCs, RBCs, glucose, platelet count and PT expression with a marked decrease in PAR-2 protein expression compared to the Cis group. The creatinine levels for both the Fund + Cis and Cis + Alt groups were found to be comparable to those of the Cis-only group. The results demonstrate that the coagulation system's activation through the stimulation of PAR-2 and fibrinogen due to Cis-induced ADAM10 protein expression mediated the apoptotic pathway, as indicated by caspase-3 expression through the p-Akt pathway. This is normally accompanied by the loss of RXR-α distal and proximal tubules as lipid droplets. When the animals were pre-treated with the anticoagulant, Fund, the previous deleterious effect was halted while the fibrinolytic agent, Alt, most of the time failed to treat Cis-induced toxicity.
急性肾衰竭（ARF）是一种有害病症，会增加死亡率、医疗成本或导致依赖透析的终末期肾病。本研究旨在比较磺达肝癸钠（Fund）预防与阿替普酶（Alt）治疗对改善顺铂（Cis）诱导的ARF的效果。将60只雄性小鼠随机均分为六组：对照组、Cis组、Alt组以及Cis + Alt组，这四组均接受10天的生理盐水注射。除对照组外，其他四组在第7天接受顺铂（30 mg/kg，腹腔注射），6小时后，Alt组静脉注射阿替普酶（0.9 mg/kg）。Fund组和Fund + Cis组连续10天腹腔注射磺达肝癸钠（5 mg/kg），Fund + Cis组在第7天接受顺铂注射。所有动物组在注射顺铂72小时后实施安乐死。与单纯Cis组相比，Fund + Cis组除尿素、血尿素氮（BUN）、尿酸、白细胞（WBC）、红细胞（RBC）、相对肾脏体重、肾脏损伤评分、葡萄糖、凝血酶原（PT）、解聚素和金属蛋白酶-10（ADAM10）、细胞外基质沉积、蛋白酶激活受体2（PAR-2）以及纤维蛋白原表达水平降低外，血小板计数、视黄酸X受体α（RXR-α）和磷酸化Akt（p-Akt）的表达水平显著升高。同时，与Cis组相比，Cis + Alt组除尿素、BUN、尿酸、WBC、RBC、葡萄糖、血小板计数和PT表达水平降低外，半胱天冬酶-3表达增加，PAR-2蛋白表达显著降低。发现Fund + Cis组和Cis + Alt组的肌酐水平与单纯Cis组相当。结果表明，Cis诱导的ADAM10蛋白表达通过刺激PAR-2和纤维蛋白原激活凝血系统，介导了凋亡途径，如通过p-Akt途径的半胱天冬酶-3表达所示。这通常伴随着RXR-α远端和近端肾小管作为脂滴的丢失。当动物用抗凝剂Fund进行预处理时，先前的有害作用停止，而纤溶药物Alt在大多数情况下未能治疗Cis诱导的毒性。
