Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt; Department of Pharmacies, Benha University Hospitals, Benha, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
Chem Biol Interact. 2021 Jan 5;333:109307. doi: 10.1016/j.cbi.2020.109307. Epub 2020 Nov 4.
Renal ischemia-reperfusion injury (R-IRI) is the main cause of acute renal failure. Carvedilol has been shown to protect against R-IRI. However, the underlying mechanisms are still not completely clarified. This study aimed to investigate the role of lipid signaling in mediating carvedilol protective effects against R-IRI in insulin-resistant mice by using two different lipid signaling modulators, quercetin and lithium chloride (LiCl). Mice were fed high-fructose, high-fat diet (HFrHFD) for 16 weeks to induce insulin resistance. At the end of feeding period, mice were randomly distributed into five groups; Sham, R-IRI, Carvedilol (20 mg/kg, i.p.), Carvedilol + Quercetin (10 mg/kg, i.p.), Carvedilol + LiCl (200 mg/kg, i.p.). R-IRI was performed by applying 30 min of unilateral renal ischemia followed by one hour of reperfusion. Quercetin and LiCl were administered 30 min before carvedilol administration and carvedilol was administered 30 min before ischemia. Changes in kidney function tests, histopathology, fibrosis area, lipid signaling, inflammatory, apoptosis and oxidative stress markers in the kidney were measured. Results showed that R-IRI decreased kidney function, impaired renal tissue integrity, modulated lipid signaling and increased renal inflammation, apoptosis and oxidative stress. Carvedilol treatment decreased the detrimental effects induced by R-IRI. In addition, pre-injection of both quercetin and LiCl potentiated the reno-protective effects of carvedilol against R-IRI independent of changes in lipid mediators like phosphatidyl inositol 4,5 bisphosphate (PIP2) and diacylglycerol (DAG). In conclusion, quercetin and LiCl potentiate the protective effects of carvedilol against R-IRI in HFrHFD-fed mice by reducing inflammation and oxidative stress independent of lipid signaling.
肾缺血再灌注损伤（R-IRI）是急性肾衰竭的主要原因。卡维地洛已被证明可预防 R-IRI。然而，其潜在机制仍未完全阐明。本研究旨在通过使用两种不同的脂质信号调节剂槲皮素和氯化锂（LiCl），研究脂质信号在介导卡维地洛对胰岛素抵抗小鼠 R-IRI 保护作用中的作用。小鼠给予高果糖、高脂肪饮食（HFrHFD）喂养 16 周以诱导胰岛素抵抗。在喂养期末，将小鼠随机分为五组：假手术组、R-IRI 组、卡维地洛（20mg/kg，腹腔注射）组、卡维地洛+槲皮素（10mg/kg，腹腔注射）组、卡维地洛+LiCl（200mg/kg，腹腔注射）组。通过单侧肾缺血 30min 后再灌注 1 小时进行 R-IRI。槲皮素和 LiCl 在给予卡维地洛前 30min 给予，卡维地洛在缺血前 30min 给予。测量肾功能试验、组织病理学、纤维化面积、肾脏中的脂质信号、炎症、细胞凋亡和氧化应激标志物的变化。结果表明，R-IRI 降低了肾功能，损害了肾脏组织完整性，调节了脂质信号，并增加了肾脏炎症、细胞凋亡和氧化应激。卡维地洛治疗降低了 R-IRI 引起的有害作用。此外，预先注射槲皮素和 LiCl 增强了卡维地洛对 R-IRI 的肾保护作用，而不改变磷脂酰肌醇 4,5 二磷酸（PIP2）和二酰基甘油（DAG）等脂质介质。总之，槲皮素和 LiCl 通过降低炎症和氧化应激增强了卡维地洛对 HFrHFD 喂养小鼠 R-IRI 的保护作用，而不依赖于脂质信号。
