Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Biomed Pharmacother. 2021 Jul;139:111488. doi: 10.1016/j.biopha.2021.111488. Epub 2021 May 3.
Despite the renal expression of PY, the purinergic receptor for adenosine diphosphate, few data are available to discuss the renotherapeutic potential of ticagrelor, one of its reversible blockers. Indeed, the tonic inhibitory effect of this receptor has been linked to the activation of exchange protein activated by cyclic adenosine monophosphate-1 (Epac-1) protein through the cyclic adenosine monophosphate cascade. Epac-1 is considered a crossroad protein, where its activation has been documented to manage renal injury models. Hence, the current study aimed to investigate the possible therapeutic effectiveness of ticagrelor, against renal ischemia/reperfusion (I/R) model with emphasis on the involvement of Epac-1 signaling pathway using R-CE3F4, a selective Epac-1 blocker. Accordingly, rats were randomized into four groups; viz., sham-operated, renal I/R, I/R post-treated with ticagrelor for 3 days, and ticagrelor + R-CE3F4. Treatment with ticagrelor ameliorated the I/R-mediated structural alterations and improved renal function manifested by the reduction in serum BUN and creatinine. On the molecular level, ticagrelor enhanced renal Epac-1 mRNA expression, Rap-1 activation (Rap-1-GTP) and SOCS-3 level. On the contrary, it inhibited the protein expression of JAK-2/STAT-3 hub, TNF-α and MDA contents, as well as caspase-3 activity. Additionally, ticagrelor enhanced the protein expression/content of AKT/Nrf-2/HO-1 axis. All these beneficial effects were obviously antagonized upon using R-CE3F4. In conclusion, ticagrelor reno-therapeutic effect is partly mediated through modulating the Epac-1/Rap-1-GTP, AKT/Nrf-2/HO-1 and JAK-2/STAT-3/SOCS-3 trajectories, pathways that integrate to afford novel explanations to its anti-inflammatory, anti-oxidant, and anti-apoptotic potentials.
尽管嘌呤能受体 ADP 的肾脏表达物 PY 存在，但关于其可逆抑制剂替格瑞洛的肾治疗潜力，相关数据仍十分有限。实际上，该受体的紧张性抑制作用已被证明与环磷酸腺苷单磷酸-1（Epac-1）蛋白通过环磷酸腺苷单磷酸级联的激活有关。Epac-1 被认为是一种交叉蛋白，其激活已被证明可用于管理肾损伤模型。因此，本研究旨在探讨替格瑞洛对肾缺血/再灌注（I/R）模型的可能治疗效果，并强调使用 R-CE3F4（一种选择性 Epac-1 阻断剂）来研究 Epac-1 信号通路的参与情况。相应地，大鼠被随机分为四组：假手术组、肾 I/R 组、I/R 后替格瑞洛治疗 3 天组和替格瑞洛+R-CE3F4 组。替格瑞洛治疗改善了 I/R 介导的结构改变，并通过降低血清 BUN 和肌酐来改善肾功能。在分子水平上，替格瑞洛增强了肾 Epac-1 mRNA 表达、Rap-1 激活（Rap-1-GTP）和 SOCS-3 水平。相反，它抑制了 JAK-2/STAT-3 枢纽、TNF-α 和 MDA 含量以及 caspase-3 活性的蛋白表达。此外，替格瑞洛增强了 AKT/Nrf-2/HO-1 轴的蛋白表达/含量。所有这些有益作用在使用 R-CE3F4 时均明显受到拮抗。总之，替格瑞洛的肾治疗作用部分是通过调节 Epac-1/Rap-1-GTP、AKT/Nrf-2/HO-1 和 JAK-2/STAT-3/SOCS-3 途径来介导的，这些途径整合起来为其抗炎、抗氧化和抗凋亡潜力提供了新的解释。
